Download Physiological and Molecular Basis of Thyroid Hormone Action

PHYSIOLOGICAL REVIEWS
Vol. 81, No. 3, July 2001
Printed in U.S.A.
Physiological and Molecular Basis
of Thyroid Hormone Action
PAUL M. YEN
Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institute
of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
Introduction
Background: Thyroid Hormone Synthesis
Multiple Thyroid Hormone Receptor Isoforms
Thyroid Hormone Receptor Functional Domains
A. DNA-binding domain
B. Ligand-binding domain
C. Hinge region
D. Amino-terminal (A/B) domain
V. Thyroid Hormone Response Elements
VI. Thyroid Hormone Receptor Complexes
VII. Phosphorylation of Thyroid Hormone Receptors
VIII. Molecular Mechanisms of Thyroid Hormone Receptor Action
A. Corepressors/basal repression
B. Coactivators/transcriptional activation
C. Cross-talk with other nuclear hormone receptors
D. Nongenomic effects of TH
IX. Thyroid Hormone Effects on Target Tissues
A. Bone
B. Heart
C. Fat
D. Liver
E. Pituitary
F. Brain
X. Resistance to Thyroid Hormone
XI. Genetically Engineered Mouse Models of Thyroid Hormone Action
XII. Conclusion
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
I.
II.
III.
IV.
1097
1098
1099
1102
1102
1102
1104
1104
1105
1106
1107
1108
1108
1111
1114
1115
1116
1116
1117
1118
1119
1120
1120
1121
1124
1126
Yen, Paul M. Physiological and Molecular Basis of Thyroid Hormone Action. Physiol Rev 81: 1097–1142, 2001.—
Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of
virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear
hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular
mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the
molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid
hormone syndrome, and genetically engineered mouse models.
I. INTRODUCTION
Thyroid hormones (THs) play critical roles in differentiation, growth, and metabolism. Indeed, TH is required
for the normal function of nearly all tissues, with major
effects on oxygen consumption and metabolic rate (375).
Disorders of the thyroid gland are among the most common endocrine maladies. Furthermore, endemic cretinhttp://physrev.physiology.org
ism due to iodine deficiency remains a public health problem in developing countries at the advent of the third
millennium. Thus the study of TH action has important
biological and medical implications.
The story of TH action is interwoven with many of
the major advances in biomedical science during the past
century. Contributions from clinical medicine, physiology, biochemistry, and molecular genetics have had major
0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
1097
1098
PAUL M. YEN
ular mechanisms of TR action. The power of molecular
genetics has greatly aided our understanding of the roles
of unliganded and liganded TRs in regulating target genes.
We have learned that there are multiple TR isoforms that
bind to TREs with variable orientation, spacing, and sequences for TRE half-sites. TRs also interact with other
nuclear proteins such as corepressors or coactivators to
form complexes that regulate local histone acetylation
and interact with the basal transcriptional machinery.
Additionally, the solution of the crystal structures of the
TR ligand-binding domain (LBD) and other nuclear hormone receptors have provided insight into some of these
complex interactions at the molecular level. The development of transgenic and knockout mouse models have
shed light on the roles of TRs in the regulation of specific
target genes and development. These findings have
greatly aided our understanding of the molecular mechanisms of TH action in normal and disease states. In particular, much has been learned about the pathogenesis of
the human genetic disorder of resistance to thyroid hormone (RTH). We review some of the major advances in
these areas by initially focusing on what is known about
the molecular mechanisms of TH action and then discuss
their implications for TH action in specific tissues, RTH,
and genetically engineered mouse models.
II. BACKGROUND: THYROID HORMONE
SYNTHESIS
TH synthesis and secretion is exquisitely regulated
by a negative-feedback system that involves the hypothalamus, pituitary, and thyroid gland [hypothalamic/pituitary/thyroid (HPT) axis] (467). Thyrotropin releasing hormone (TRH) is a tripeptide (PyroGlu-His-Pro) synthesized
in the paraventricular nucleus of the hypothalamus. It is
transported via axons to the median eminence and then to
the anterior pituitary via the portal capillary plexus. TRH
binds to TRH receptors in pituitary thyrotropes, a subpopulation of pituitary cells that secrete thyroid stimulating hormone (TSH). TRH receptors are members of the
seven-transmembrane spanning receptor family and are
coupled to Gq11. TRH stimulation leads to release and
synthesis of new TSH in thyrotropes. TSH is a 28-kDa
glycoprotein composed of ␣- and ␤-subunits designated
as glycoprotein hormone ␣- and TSH ␤-subunits. The
␣-subunit also is shared with other hormones such as
luteinizing hormone, follicle stimulating hormone, and
chorionic gonadotropin. Both TRH and TSH secretion are
negatively regulated by TH. An important mechanism for
the negative regulation of TSH may be the intrapituitary
conversion of circulating T4 to T3 by type II deiodinase.
Additionally, somatostatin and dopamine from the hypothalamus can negatively regulate TSH secretion.
TSH is the primary regulator of TH release and se-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
impacts on our understanding of TH action (376, 551). The
following outline sketches only some of the many early
contributions to our knowledge.
In 1888, the Clinical Society of London published the
definitive report that first linked cretinism and adult hypothyroidism to the destruction of the thyroid gland
(97a). Soon afterward, thyroid extracts from sheep were
used for the treatment of hypothyroidism. Around this
time, Emil Kocher performed some of his pioneering studies on the pathology and surgery of the thyroid gland for
which he was awarded the Nobel prize in medicine in
1909. In 1914, Kendall (241) isolated 3,5,3⬘,5⬘-tetraiodo-Lthyronine (T4) from thyroid extracts, and almost 40 years
later, Gross and Pitt-Rivers (178) synthesized 3,5,3⬘-triiodo-L-thyronine (T3) and demonstrated its presence in
human plasma and its ability to prevent goiter in thiouracil-treated rats. Over the ensuing years, the metabolic and
oxygen consumption effects of THs as well as its effects
on development, particularly in amphibians, were appreciated (59, 79, 463).
In the 1960s, Tata and co-workers (509, 510) first
suggested that THs might be involved in the transcriptional regulation of target genes. These investigators observed that T3 treatment of hypothyroid rats induced a
rapid increase in RNA synthesis in the liver which preceded new protein formation and mitochondrial oxidation (509, 510). The groups of Oppenheimer (372) and
Samuels (441) then used radiolabeled TH to demonstrate
specific nuclear binding sites in different T3-sensitive tissues, and thus provided the first evidence for TH receptors (TRs). Moreover, T3 binding was observed in almost
all tissues (377). Attempts to purify these receptors biochemically were only partially successful; however, photoaffinity labeling of nuclear extracts demonstrated different-sized receptors and raised the possibility of
multiple TR isoforms (123, 384). Studies on T3 induction
of the rat growth hormone (GH) gene transcription suggested that TRs recognized enhancer sequences or TH
response elements (TREs), similar to steroid hormone
receptors (101, 281, 282, 440). Thus TRs behaved similar
to steroid hormone receptors with respect to nuclear site
of action, recognition of specific DNA sequences, and
ligand-dependent regulation of transcription. In 1985, the
glucocorticoid receptor was cloned and, surprisingly, had
homology with a known viral oncogene product, v-erbA,
that in conjunction with v-erbB, can cause erythroblastosis in chicks (209). Subsequent cloning of the estrogen
receptor suggested that there was a family of nuclear
hormone receptors (174). A year later, the laboratories of
Evans (545) and Vennstrom (444) ushered in the molecular era of TH action when they cloned two different TR
isoforms and showed they were the cellular homologs of
v-erbA.
Since the molecular cloning of TRs 15 years ago,
there has been an explosion of information on the molec-
Volume 81
July 2001
1099
THYROID HORMONE ACTION
Type I deioidinase is found in peripheral tissues such as
liver and kidney and is responsible for the conversion of
the majority of T4 to T3 in circulation. Type II deiodinase
is found in brain, pituitary, and brown adipose tissue and
primarily converts T4 to T3 for intracellular use. These
deiodinases recently have been cloned and demonstrated
to be selenoproteins (280). 5⬘-Deiodination by type I deiodinase and type III deioidinase, which is found primarily
in placenta, brain, and skin, leads to the generation of rT3,
the key step in the inactivation of TH. rT3 and T3 can be
further deiodinated in the liver and are sulfo- and glucuronide-conjugated before excretion in the bile (124).
There also is an enterohepatic circulation of TH as intestinal flora deconjugates some of these compounds and
promotes the reuptake of TH.
Although THs may exert their effects on a number of
intracellular loci, their primary effect is on the transcriptional regulation of target genes. Early studies showed
that the effects of THs at the genomic level are mediated
by nuclear TRs, which are intimately associated with
chromatin and bind TH with high affinity and specificity
(375, 440). Similar to steroid hormones that also bind to
nuclear receptors, TH enters the cell and proceeds to the
nucleus (Fig. 2). It then binds to TRs, which may already
be prebound to TREs located in promoter regions of
target genes. The formation of ligand-bound TR complexes that are also bound to TREs is the critical first step
in the positive or negative regulation of target genes and
the subsequent regulation of protein synthesis. Given
their abilities to bind both ligand and DNA as well as their
ability to regulate transcription, TRs can be regarded as
ligand-regulatable transcription factors.
III. MULTIPLE THYROID HORMONE
RECEPTOR ISOFORMS
In 1986, the laboratories of Vennstrom (444) and
Evans (545) independently cloned cDNAs encoding two
different TRs from embryonal chicken and human placental cDNA libraries. Several unexpected findings stemmed
from their landmark work. First, they demonstrated by
amino acid sequence comparison that TRs are the cellular
homologs of the viral oncogene product v-erbA. Second,
TRs were shown to have amino sequence homology with
steroid hormone receptors. This was initially surprising
FIG.
mones.
1. Structure of thyroid hor-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
cretion. It also has a critical role in thyroid growth and
development. TSH binds to the TSH receptor (TSHr),
which also is a seven-transmembrane spanning receptor
coupled to Gs (255, 382). Activation of TSHr by TSH or
autoantibodies in Graves’ disease leads to an increase in
intracellular cAMP and stimulation of protein kinase Amediated pathways. A number of thyroid genes, including
Na⫹/I⫺ symporter (NIS), thyroglobulin (Tg), and thyroid
peroxidase (TPO), are stimulated by TSH and promote
the synthesis of TH. Of note, activating mutations in TSHr
and Gs have been described in autonomously functioning
thyroid nodules and familial congenital hyperthyroidism
(381, 383).
The THs, T4 and the more potent T3, are synthesized
in the thyroid gland (Fig. 1). Iodide is actively transported
and concentrated into the thyroid by NIS (102, 475). The
trapped iodide is oxidized by TPO in the presence of
hydrogen peroxide and incorporated into the tyrosine
residues of a 660-kDa glycoprotein, Tg. This iodination of
specific tyrosines located on Tg yields monoiodinated and
diiodinated residues (MIT, monoiodo-tyrosines; DIT, diiodo-tyrosines) that are enzymatically coupled to form T4
and T3. The iodinated Tg containing MIT, DIT, T4, and T3,
then is stored as an extracellular storage polypeptide in
the colloid within the lumen of thyroid follicular cells.
Genetic defects along the synthetic pathway of THs have
been described in humans and are major causes of congenital hypothyroidism in iodine-replete environments
(117, 261).
The secretion of THs requires endocytosis of the
stored iodinated Tg from the apical surface of the thyroid
follicular cell (511). The internalized Tg is incorporated in
phagolysosomes and undergoes proteolytic digestion, recapture of MIT and DIT, and release of T4 and T3 into the
circulation via the basal surface. The majority of released
TH is in the form of T4, as total serum T4 is 40-fold higher
than serum T3 (90 vs. 2 nM). Only 0.03% of the total serum
T4 is free (unbound), with the remainder bound to carrier
proteins such as thyroxine binding globulin (TBG), albumin, and thyroid binding prealbumin. Approximately 0.3%
of the total serum T3 is free, with the remainder bound to
TBG and albumin. It is the free TH that enters target cells
and generates a biological response.
The major pathway for the production of T3 is via
5⬘-deiodination of the outer ring of T4 by deiodinases and
accounts for the majority of the circulating T3 (50, 256).
1100
PAUL M. YEN
Volume 81
FIG. 2. General model for thyroid hormone action in the nucleus. TR, thyroid hormone receptor; RXR, retinoid X receptors.
cies such as amphibians, chick, mouse, rat, and human
(284). Both TR isoforms bind T3 (reported dissociation
constant values between 10⫺9 and 10⫺10 M) and mediate
TH-regulated gene expression (148, 340, 449). In mammalian species, TR␣-1 and TR␤-1s range from 400 to slightly
over 500 amino acids in size (284, 289) and contain highly
homologous DNA-binding domains and LBD (Fig. 3).
In addition to two separate genes that encode TRs,
there is additional heterogeneity of TRs due to alternative
splicing (220, 292, 330, 349). Alternative splicing of the
initial RNA transcript of the TR␣ gene generates two
mature mRNAs that each encode two proteins: TR␣-1 and
c-erbA␣-2. In the rat, these proteins are identical from
amino acid residues 1–370, but their respective sequences
diverge markedly thereafter (Fig. 3). Consequently,
FIG. 3. Comparison of amino acid homologies and their functional properties among TR isoforms. The length of
receptors is indicated just above the receptor diagrams, and the percent amino acid homology with TR␤-2 is included
in the receptor diagrams.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
since T3 and cholesterol-derived steroids are structurally
different ligands. However, in the ensuing years, TRs have
been shown to belong to a large superfamily of nuclear
hormone receptors that include the steroid, vitamin D,
and retinoic acid receptors as well as “orphan” receptors
for which there are no known ligand or function (35, 285).
TRs share a similar domain organization with other family
members as they have a central DNA-binding domain
containing two “zinc fingers” and a carboxy-terminal LBD.
These initial studies also suggested that there were multiple TR isoforms. Subsequent work by many groups has
confirmed that there are two major TR isoforms encoded
on separate genes, designated as TR␣ and TR␤, encoded
on human chromosomes 17 and 3, respectively (284).
Moreover, these multiple isoforms exist in different spe-
July 2001
THYROID HORMONE ACTION
Careful low-stringency hybridization studies so far
have not yielded any additional TR isoforms. Double TR␣
and TR␤ knockout mice are viable, and these mice did not
have detectable [125I]T3 binding in nuclear extracts of
several tissues (171, 316a). However, a number of short
forms of TR␣ and TR␤ generated by alternative splicing of
mRNA or by use of internal translational start sites have
been found in embryonic stem cells and in fetal bone cells
and may have biological significance (41, 75, 553, 567).
The identification of a novel estrogen receptor isoform
(ER␤) 10 years after the discovery of ER␣ serves as a
cautionary warning to remain open to the possibility of
novel TR isoforms, particularly in restricted tissues or
during transient periods in fetal development (265).
The regulation of the TR mRNAs is isoform and cell
type dependent. In the intact rat pituitary, T3 decreases
TR␤-2 mRNA, modestly decreases TR␣-1 mRNA, and
slightly increases rat TR␤-1 mRNA (204). Despite these
opposing effects, the total T3 binding decreases by 30% in
the T3-treated rat pituitary. Similar findings also were
observed in GH3 cells, a somatolactotropic rat cell line
(205). In other tissues, T3 slightly decreases TR␣-1 and
c-erbA␣-2 mRNA except in the brain where c-erbA␣-2
levels are unaffected. TR␤-1 mRNA is minimally affected
in nonpituitary tissues. Additionally, the hypothalamic tripeptide TRH decreases TR␤-2 mRNA, slightly decreases
TR␣-1 mRNA, and minimally affects TR␤-1 mRNA in GH3
cells (230). Retinoic acid blunts the negative regulation by
T3 in these cells (114, 231). Additionally, in patients with
nonthyroidal illness in which their circulating free T3 and
T4 levels were decreased, TR␣ and TR␤ mRNAs were
increased in peripheral mononuclear cells and liver biopsy specimens (556). Thus induction of TR expression
may compensate for decreased circulating TH levels in
these patients.
Each of the TR isoforms found in human, rat, and
mouse are highly homologous with respect to their amino
acid sequences (284). This conservation among species
suggests that there may be important specialized functions for each isoform (109). However, the evidence for
isoform-specific functions has been scant since most cotransfection experiments have failed to show important
functional differences. Nonetheless, recent studies have
suggested that TR␤-1 may exhibit isoform-specific regulation of the TRH and myelin basic protein genes, and
TR␤-2 may play an important role in the regulation of the
GH and TSH␤ gene expression in the pituitary (4, 129, 208,
283, 305). Future studies with TR knockout mice, antisense oligonucleotides in tissue culture, and isoform-specific ligands, perhaps in conjunction with cDNA microarrays, should shed more light on the respective roles of TR
isoforms in regulating specific target genes (24, 86, 136,
151).
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
c-erbA␣-2 cannot bind T3 because it contains a 122-amino
acid carboxy terminus that replaces a region in TR␣-1 that
is critical for TH binding. Additionally, c-erbA␣-2 binds
TREs weakly but cannot transactivate TH-responsive
genes. Thus TR␣-1, but not c-erbA␣-2, is an authentic TR.
Indeed, c-erbA␣-2 may act as an inhibitor of TH action
possibly by competing for binding to TREs (253, 291). The
TR␣-1 and c-erbA␣-2 system, then, represents one of the
first examples in which multiple mRNAs generated by
alternative splicing encode proteins that may be antagonistic to each other. Mitsuhashi et al. (330) also have
described a second TR␣ variant, c-erbA␣-2V, in which the
first 39 amino acids of the divergent sequence are missing
(330). Its function currently is unknown. Yet another interesting feature of the TR␣ gene is the employment of the
opposite strand to encode a gene product, rev-erbA. ReverbA mRNA contains a 269-nucleotide stretch which is
complementary to the c-erbA␣-2 mRNA due to its transcription from the DNA strand opposite of that used to
generate TR␣-1 and c-erbA␣-2 (293, 331). This protein also
is a member of the nuclear hormone receptor superfamily. It is expressed in adipocytes and muscle cells, and can
bind to TREs and retinoic acid response elements
(RAREs) and repress gene transcription (190, 477, 597).
However, rev-erbA should be considered an orphan receptor since its cognate ligand and function are not
known. One potential role for rev-erbA may be to regulate
the splicing that generates c-erbA␣-2 as increased levels
of rev-erbA mRNA correlate with increased TR␣-1 mRNA
relative to c-erbA␣-2 (80, 224, 290).
There also are two TRs derived from the TR␤ gene
(205, 284). This gene contains two promoter regions each
of which is vital for the transcription of an mRNA coding
for a distinctive protein. By the use of alternate promoter
choice, one or both of the coding mRNAs are generated
(566). The resultant TR␤ isoforms are designated as
TR␤-1 and TR␤-2. The amino acid sequences of the DNA
binding, hinge region, and LBDs of these two TR␤s are
identical, but the amino-terminal regions bear no homology (Fig. 3). Both are authentic receptors as they bind
TREs and TH with high affinity and specificity and can
mediate TH-dependent transcription. The expression of
the two TR␤ isoforms may be regulated by pituitaryspecific transcription factors such as Pit-1 (566).
Both TR␣-1 and TR␤-1 mRNAs and proteins are
ubiquitously expressed in rat tissues (204). However,
TR␣-1 mRNA has highest expression in skeletal muscle
and brown fat, whereas TR␤-1 mRNA has highest expression in brain, liver, and kidney. In contrast to the
other TR isoforms, TR␤-2 mRNA and protein have tissue-specific expression in the anterior pituitary gland
and specific areas of the hypothalamus as well as the
developing brain and inner ear (47, 48, 98, 204, 590). In
the chick, TR␤-2 mRNA also is expressed in the developing retina (473).
1101
1102
PAUL M. YEN
Volume 81
FIG. 4. General organization of major
TR domains and functional subregions.
IV. THYROID HORMONE RECEPTOR
FUNCTIONAL DOMAINS
A. DNA-Binding Domain
The DBD is located in the central portion of TR and has
two zinc fingers, each composed of four cysteines coordinated with a zinc ion (Fig. 5). The integrity of each zinc
finger is critical, as deletion of zinc fingers or amino acid
substitution of these cysteine residues abrogates DNA-binding and transcriptional activity of steroid hormone receptors
and TRs (173, 345, 460, 592). Within the first zinc finger, there
is a “P box,” comprised of amino acids located between and
just distal to the third and fourth cysteines, which is similar
to that of estrogen recetors (ERs), retinoic acid receptors
(RARs), retinoid X receptors (RXRs), and vitamin D recep-
B. Ligand-Binding Domain
The LBD not only is necessary for TH binding but
also plays critical roles for dimerization, transactivation,
FIG. 5. DNA-binding domains of human TR␤. Schematic drawing of the two
zinc fingers of human TR␤ and the various subregions within the DNA-binding
domains. Squares, TR/RXR heterodimerization contacts; ovals, direct base contacts; solid circles, direct phosphate contacts. [From Rastinejad et al. (413).
Reprinted by permission from Nature,
copyright 1995 Macmillan Magazines
Ltd.]
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
Mutational analyses of TRs and comparisons with
other members of the nuclear hormone receptor superfamily have yielded much information on the structural
features of TRs (284, 583). All TRs have a similar domain
organization as that found in all nuclear hormone receptors: an amino-terminal A/B domain, a central DNA-binding domain containing two “zinc fingers” (DBD), a hinge
region containing the nuclear localization signal, and a
carboxy-terminal LBD (Fig. 4). It should be noted that
each of these domains and regions may subserve multiple
functions, and thus their names may only reflect the first
function ascribed to them.
tors (VDRs) (106, 317, 531). This critical region has been
shown to be important in sequence-specific recognition of
hormone response elements by different members of the
nuclear hormone superfamily and contacts nucleic acids
and phosphate groups within the major groove of the TRE
(353, 413). Additionally, there are other important contact
points within the minor groove of the TRE just downstream
from the second zinc finger (A-box region). Also, as discussed below, TRs can heterodimerize with RXRs and can
bind to TREs that are arranged as direct repeats separated
by a four nucleotide gap. These TR/RXR heterodimers bind
to TREs with a 5⬘ to 3⬘ polarity with TR in the downstream
position (268, 391, 586). The ability to heterodimerize with
RXR is critical for TR binding to the asymmetric TRE, as
dimerization contacts stabilize the DNA binding and determine the spacing between half-sites. Within the DBD, there
are dimerization interfaces in the TR just upstream of the
first zinc finger, within the first zinc finger, and in a subregion distal to the second zinc finger (T box). The RXR
dimerization surfaces are located in the second zinc finger
including an arginine located in the D box, a region which
previously has been shown to be important for distinguishing spacing between half-sites of hormone response elements (315, 531).
July 2001
THYROID HORMONE ACTION
FIG. 6. TR␣-1 ligand-binding domain crystal structure. Dark mass
represents ligand. ␣-Helices are indicated. [From Wagner et al. (544).
Reprinted by permission from Nature, copyright 1995 Macmillan Magazines Ltd.]
lying in a groove between helices 3 and 5. Thus the
relative positions of helix 12 and the boundary helices
may determine whether coactivators can interact with
TR. Indeed, studies using TR-LBD mutants based on the
TR-LBD crystal structure have confirmed these regions
for interacting with the coactivator GRIP-1 (107, 134).
TR␣ and TR␤-1 isoforms can bind T3 and various TH
analogs with subtle differences in affinity. TR␣ binds T3
with slightly higher affinity than TR␤-1 (449). Triac (3,5,3⬘triiodothyroacetic acid) binds TR␣-1 with similar affinity
as T3 and binds TR␤-1 with two- to threefold higher
affinity than T3. Several novel thyromimetics have been
designed which bind TR␤-1 (GC-1 and CGS 23425) with
10- to 50-fold higher affinity (86, 512). The transcriptional
activities of these isoform-specific compounds parallel
their binding affinities and may offer novel therapeutic
treatments of diseases such as hypercholesterolemia
while sparing the heart (which contains mostly TR␣) from
side effects. The crystal structures of hTR␣ and hTR␤
LBDs have been solved and may provide important information for designing even more selective thyromimetics
in the future (419).
The LBD also is involved in several other important
receptor functions. Scattered throughout the LBD are
discontinuous heptad repeats that have been proposed to
form hydrophobic interfaces for TR homo- and heterodimerization (145). Mutations in the ninth heptad repeat region have selectively decreased TR homo- and
heterodimer formation, suggesting that there may be different subregions of the LBD that are important for TR
dimerization (21, 140, 344, 592). Indeed, the TR␣-1 LBD
crystal structure demonstrates that there is a hydrophobic
surface in the ninth heptad repeat region that could serve
as a potential dimerization interface (544). A natural TR␤
mutation from a patient with resistance to TH at amino
acid 316 also displayed decreased homodimer formation,
suggesting that additional regions of the LBD may be
important for dimerization (189, 360, 592). The relative
contributions to dimerization by the LBD and DBD interfaces may depend on the receptor. A recent study suggests that a region that contains the ninth heptad region
called the “I box” may be important for RAR heterodimerization with RXR in solution and for binding to direct
repeats of variable spacing (392). On the other hand, the
DBD dimerization interface may be important for dictating binding to direct repeats of a specific spacing (in this
case, a 5-nucleotide gap). Recent studies suggest that the
ninth heptad region may be more important for heterodimerization of TR␣-1, whereas the DBD may play the
dominant role for c-erbA␣-2 because it lacks a complete
ninth heptad region due to alternative splicing (416, 568).
Baniahmad et al. (27) used a GAL4-fusion system to
identify at least three transcriptional activation regions in
the LBD and designated them as ␶2, ␶3, and ␶4 (27).
Uppalari and Towle (534) also have used a yeast trans-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
and basal repression by unliganded TR. The recent solutions of the crystal structures of the liganded TR␣-1,
unliganded RXRa, and RAR␥ LBDs have greatly aided our
understanding of its role on these functions and the attendant conformational changes that occur when T3 binds
to the receptor (Fig. 6) (46, 417, 544). Ligand is buried
deep within a hydrophobic pocket in the LBD formed by
discontinuous stretches that span almost the entire LBD.
In particular, the most carboxy-terminal region (Helix 12)
contributes its hydrophobic surface as part of the ligandbinding cavity. The hydrophobic residues face inward,
whereas the conserved glutamate faces outward. The cavity also is bounded by hydrophobic surfaces from helices
3, 4, and 5. Although the crystal structure of unliganded
TR has yet to be solved, the crystal structure of unliganded RXR␣ shows that helix 12 projects into the solvent.
Thus it is likely that helix 12 undergoes major conformational changes upon ligand binding, from a more open
conformation to a closed one, which has been likened to
a “mouse trap” mechanism. In an analogous manner, estrogen-bound LBD shows a similar structure as ligandedTR LBD with helix 12 facing inward (61). However, helix
12 of raloxifene-bound ER LBD is in a different position,
1103
1104
PAUL M. YEN
C. Hinge Region
The hinge region between the DBD and T3-binding
domain likely contains an amino acid sequence that is
FIG. 7. Comparison of AF-2 regions of nuclear hormone receptors.
Conserved ␾␾xE␾␾ sequences are underlined.
associated with nuclear localization (126). This lysine-rich
sequence is highly conserved among nuclear hormone
receptors and bears homology with the simian virus 40 T
antigen nuclear localization sequence. TRs are likely imported into the nucleus shortly after synthesis as they are
predominantly found in the nucleus and can bind DNA,
even in the absence of hormone. Furthermore, unlike
some steroid hormone receptors, TRs do not associate
with cytoplasmic heat shock proteins (103). Recent studies using green fluorescent fusion proteins of wild-type
TR␤ and TR␤ hinge region mutants demonstrated this
region may be important for T3-mediated translocation of
TR into the nucleus (605).
The hinge region also has additional properties. The
laboratories of Evans (83) and Rosenfeld and co-workers
(211) identified corepressor proteins that can interact
with unliganded TRs, RARs, and v-erbA and mediate repression of basal transcription by these receptors and
v-erbA (see sect. VIII). Mutations in the TR␤-1 hinge region
abrogate the basal repression by corepressor. Additionally, a v-erbA mutation in the hinge region that abrogates
its oncogenic potential also failed to interact with a corepressor, silencing mediator for RAR and TR (SMRT) (83).
These findings suggest that the hinge region of unliganded
TRs located on helix 1 may serve as a contact surface with
corepressors or have allosteric effects on their interaction. Recent work by several groups also suggest that
sequences within helices 3, 5, and 6 of the LBD contribute
to corepressor binding (214, 348, 390).
D. Amino-Terminal (A/B) Domain
The amino-terminal regions have variable lengths
and divergent sequences among the TR isoforms. Even
among different species, this region is less well conserved
for a given TR isoform, because the rat and human TRs
are 97 and 99% identical in their DBDs and LBDs, respectively, but only 85% identical in their amino-terminal domains (254). The role(s) of the amino-terminal domain is
poorly understood. Studies of the glucocorticoid receptor
have suggested that there is a major activation function
domain, ␶1, which has structural similarities with viral
acidic activator proteins such as VP16 (209). Previous
work by Tora and co-workers (524, 525) with progesterone and truncated estrogen receptors also have suggested
that the amino-terminal domain may modulate cell-specific and promoter-specific transcription. Cotransfection
studies generally have demonstrated only a few examples
of isoform-specific transcriptional activation by TRs. Farsetti et al. (129) have shown that TR␤-1 has higher transcriptional activity than TR␣-1 via a myelin basic protein
TRE reporter in the context of the native promoter, but
not with the viral thymidine kinase promoter (129). Jeannin et al. (224) observed similar TR␤-1-specific effects on
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
fection system to describe several activation regions in
TR␤-1 LBD as well as in the hinge region (534). In particular, ␶4 located near the carboxy terminus has high homology with LBD sequences found in other nuclear hormone receptors previously designated as the activation
function-2 (AF-2) domain (Fig. 7). This sequence located
within helix 12 has been shown to be important for liganddependent transcriptional activation by other nuclear hormone receptors (31, 105, 278). Recently, Chatterjee and
co-workers (521) have made point mutations in this region and have observed normal T3 binding and DNA binding, but no transcriptional activation, using a GAL4/TR␤
LBD fusion protein system (521). As discussed earlier,
helix 12 likely undergoes major conformational changes
upon ligand binding (419). Studies with steroid hormone
receptors and TRs have demonstrated that the AF-2 domain is important for interactions with coactivators such
as SRC-1 and related family members (419). Interestingly,
mutations in the AF-2 region of the TR LBD had modest
effects on T3-dependent interaction of the coactivator
TRAM-1 (SRC-3), whereas a mutation in helix 3 of the TR
LBD severely impaired T3-dependent interaction with
TRAM-1 but had little effect on interaction with SRC-1
(503). Ligand-dependent GRIP-1 (SRC-2) interactions with
TR involve helices 3, 5, 6, and 12 (134). These findings
suggest that different subregions of TR may differentially
contribute to interaction with specific coactivators. Additionally, several groups reported that corepressors may
interact with sequences on helices 3, 5, and 6 that overlap
sequences involved in interacting with coactivators (214,
348, 390). Several mutations from patients with resistance
to TH and artificial mutations in helices 3 and 5 do not
interact with coactivators or corepressors (97, 348, 390).
Volume 81
July 2001
THYROID HORMONE ACTION
(208). Recent studies showed that the amino terminus of
TR␤-2 may interact with the silencing domain of the corepressor, SMRT, and thereby block the recruitment of
other components of the corepressor complex (575). Finally, the amino-terminal domain of TR also may influence the conformation of the DBD and the repertoire of
TREs to which it can bind (184, 232).
V. THYROID HORMONE RESPONSE ELEMENTS
Steroid hormone receptors bind as homodimers to
conserved palindromic hormone response elements that
mediate hormone regulation of target genes (160). In
contrast, TRs can bind to TREs as monomers, homodimers, and heterodimers in vitro. In general, most of
these TREs are located upstream from the minimal promoter, but in certain cases, also can be located in 3⬘flanking sequences downstream from the coding region
(40, 600). Mutational analyses of the rat growth hormone
gene TRE, and sequence comparison among known TREs
from other T3-responsive genes, have suggested a putative
consensus hexamer half-site sequence of (G/A)GGT(C/
G)A (84, 555). However, there can be considerable variation found in primary nucleotide sequences of TREs as
well as the number, spacing, and orientation of their
half-sites (555). In particular, TRs can bind to TREs in
which half-sites are arranged as palindromes (TREpal),
direct repeats (DRs), and inverted palindromes (IPs). The
optimal spacing for these half-site arrangements are zero,
four, and six nucleotides, respectively (TREpal0, DR4, and
IP6) (Fig. 8). Almost all positively regulated target genes
contain two or more half-sites; however, TRs can activate
transcription via an artificial single octamer half-site, perhaps even as monomers (240).
Approximately 30 natural TREs have been described
so far with DRs, followed by IPs, as the most common
motifs (555). Several groups also have observed that TR
homo- and heterodimers bind to TREs arranged as IPs
and DRs better than palindromes (17, 268, 333, 588). In the
case of DRs, it has been shown that VDRs preferentially
FIG. 8. Half-site orientation and optimal nucleotide
spacing between half-sites. N refers to nucleotides, and
arrows show direction of half-sites on the sense strand.
TRE, thyroid hormone response element.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
myelin basic protein, but not on malic enzyme, gene expression suggesting that isoform-specific gene regulation
may occur in a subset of target genes (224). Similar TR␤1-specific effects on the regulation of the TRH promoter
also have been observed (181, 305). TR␤-2 may have a
more potent role in the negative regulation of glycoprotein ␣-subunit and TSH␤ than other TR isoforms (208,
275). In particular, TR␤-2 mediates strong ligand-independent activation of negatively regulated target genes such
as glycoprotein hormone ␣-subunit and TSH␤ (275). Indeed, recent studies of TR knockout mice have implicated
TR␤-2 as the major TR isoform in negative regulation of
TSH (3).
The role of the amino-terminal domain in transcriptional activation is still controversial. Some studies have
shown that deletion of the amino-terminal domain of
TR␤-1 had no effect on T3-dependent transcriptional activation by TR␤-1 (516, 592), suggesting that it does not
contain a major activation function domain like the glucocorticoid receptor. On the other hand, studies of TR␣-1
and TR␤-1 from several species have shown that the
amino-terminal domain may be important for transcriptional activation and interactions with the general transcription factor TFIIB (25, 183, 520). Additionally, it has
been shown that the chick TR␤-2 amino-terminal region
may have two activation domains (472). A minimal subregion of amino acids 21–50 allows human TR␤-2 to interact with coactivators in the absence of ligand and may
account for the ligand-independent activation of some
positively regulated target genes (358). However, one
study of the amino-terminal region suggested that rat
TR␤-2 does not appear to have a strong activation domain
in the amino-terminal region (520), whereas other studies
have shown that TR␤-2 transactivates similar to TR␤-1
(205, 478). It is possible that differences in species, cell
types, TREs, and minimal promoters may account for
these different observations (129, 491, 580). The aminoterminal domain also may modulate ligand-independent
repression via positively regulated TREs because one
study showed that TR␣-1 is more potent than TR␤-1 or
TR␤-2 in mediating basal repression in the absence of T3
1105
1106
PAUL M. YEN
corepressors that link the liganded TR/RXR heterodimer
with the transcriptional machinery. In this connection,
Kurokawa et al. (267) demonstrated that RAR/RXR heterodimers bound to DR1 and DR5 with different polarities. In the former case, they remained bound to a corepressor and mediated constitutive basal repression, and
in the latter case, they dissociated from corepressor in the
presence of all-trans-retinoic acid and mediated transcriptional activation. Similarly, it has been shown that
the TRE sequence can affect corepressor release from TR
in the presence of ligand (368).
VI. THYROID HORMONE RECEPTOR
COMPLEXES
Early studies of TR binding to specific DNA sequences utilized methods such as the avidin-biotin complex/DNA (ABCD) assay that did not allow direct visualization of TR complexes bound to DNA (63, 161, 585).
However, successful employment of electrophoretic mobility shift assays (EMSAs) demonstrated that TRs could
bind to synthetic and natural TREs as monomers, homodimers, and heterodimers in vitro (144, 288, 557, 584).
TR␤-1 may have a greater tendency than TR␣-1 to form
homodimers on several different TREs, suggesting that
these two TR isoforms may have different dimerization
potentials (109, 607). Domain swap experiments have
suggested that the amino-terminal region of TR␣-1 may
inhibit homodimer formation via an allosteric mechanism
(208).
Initially, TRs were thought to mediate their effects on
transcription as homodimers, similar to steroid hormone
receptors. However, two groups observed that TRs surprisingly heterodimerized with proteins from pituitary
and liver nuclear extracts (63, 341). These proteins were
called TR auxiliary proteins (TRAPs) and enhanced TR
binding to TREs (63, 341). Because these proteins were
expressed in nuclear extracts from many different tissues
and species (63, 287, 341, 494), TR/TRAP heterodimers
potentially could be formed in all cells that contain TRs.
Because these heterodimers appeared to bind better to
TREs than TR homodimers, it was speculated that they
played a role in T3-regulated transcription.
Several groups showed that TRs heterodimerize with
RXRs, members of the nuclear hormone receptor superfamily which have high homology with RARs (250, 300,
321, 589, 594, 602). RXRs bind their cognate ligand, 9-cisretinoic acid, with high affinity (202, 304). They can form
homodimers as well as heterodimers with RARs, VDRs,
and peroxisome proliferator activated receptors (PPARs)
(160). Several lines of evidence suggest that RXRs are the
major TRAPs and thus play a critical role in T3-mediated
transcription. First, they were observed to enhance TR
binding to TREs. Second, studies using anti-RXR antibod-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
transactivate via reporter vectors containing DRs with a
three-nucleotide gap (DR3), TRs via a four-nucleotide gap
(DR4), and RARs via a gap of five nucleotides (DR5),
according to a “3– 4 –5” rule (160, 532). Heterodimerization with RXR and specific DNA contact points in the
DBD may play important roles in determining heterodimer spacing on direct repeats (153, 160, 413). However, the DNA binding and transcriptional activation via
these elements do not appear to be absolutely receptor
specific because TRs can bind and transactivate weakly
on DR5 and DR6, and RARs can bind and transactivate on
DR4 (557, 588). VDRs can bind to DR4 and DR5 (587) but
cannot transactivate via these HREs. However, VDR has
dominant negative activity on T3 and RA-mediated transcription via these elements. Additionally, the primary
sequence of the half-site may be important in maintaining
receptor-specific binding to DRs as mutation of the third
nucleotide of the half-site hexamer from a G to a T
enabled VDR binding and ligand-mediated transactivation
via a DR4 (418). It also has been shown that flanking and
spacing sequences in TREs can affect DNA-binding and
transcriptional activation, either by making contacts with
TR or local DNA bending (216, 240, 242, 244).
TRs can form heterodimers with RXRs, which also
are members of the nuclear hormone receptor superfamily (see below). This enables TR complexes to bind to
TREs in a specific orientation relative to the minimal
promoter. Palindromic and inverted palindromic TRE
half-site sequences are symmetric and thus do not dictate
a particular heterodimer orientation on the TRE. On the
other hand, TRE half-sites in DR4 have a 5⬘ to 3⬘ polarity
so the direct repeat motif could specify the heterodimer
orientation on the TRE. Several approaches have been
used to study this issue. Mutant TRs or RXRs containing
amino acid substitutions in the P box of the first zinc
finger of the DNA-binding domain that allow preferential
binding to a glucocorticoid hormone response element
(GRE) half-site have been used to study TR/RXR heterodimer binding to hybrid response elements containing
TRE and GRE half-sites (268, 391, 586). These results
showed that TR binds to the downstream half-site and
RXR to the upstream half-site when TR/RXR heterodimer
binds to DR4. Methylation interference studies also
showed that TR␣-1 and TR␣-1/RXR preferentially bound
to the downstream half-sites of DR4 and the IP F2 (216).
The apparent polarity of TR/RXR complexes on F2 may be
due to degeneracy of one of the half-site sequences or
possibly contributions by the flanking and spacing sequences. Cotransfection studies in which the orientation
of these TREs were reversed also decreased T3-mediated
transcriptional activity (216). Taken together, these findings suggest that TR/RXR heterodimers bind with a specific polarity which, in turn, can modulate transcriptional
activity. This “shape” of the TR complex may be important in protein-protein interactions with coactivators and
Volume 81
July 2001
THYROID HORMONE ACTION
target genes in the absence of T3, which then dissociates
from the TRE in the presence of T3.
Cross-linking and coimmunoprecipitation studies
suggest that TR monomers and TR/RXR heterodimers
exist in solution, whereas TR homodimers form weakly in
solution (268, 288, 581). T3 and 9-cis-retinoic acid promote dimerization in solution, and thus may preform a
transcriptionally active complex before DNA binding (95,
234). It appears that dimerization promotes DNA binding
(392), and DNA binding enhances dimerization (56, 366,
581).
VII. PHOSPHORYLATION OF THYROID
HORMONE RECEPTORS
Recently several groups also have observed that increasing the phosphorylation state of cells can enhance
T3-mediated transcriptional activation of target genes
(229, 308, 496). The mechanisms for this enhanced transcriptional activation are not known but may involve
phosphorylation of TR, RXR, or coactivators. In support
of the potential role of TR phosphorylation in transcriptional activation, it recently has been demonstrated that
TR can be phosphorylated in vitro and in vivo (165, 167,
308, 492). Chick TR␣-1 has at least two serine phosphorylation sites in the amino-terminal A/B domain, but the
functional role(s) is not known (167). Additionally, these
sites do not appear to be conserved across species. The
human TR␤-1 can be phosphorylated in vivo and in vitro
(308), although the phosphorylation sites have not been
determined. Two groups have used HeLa cytosol extract
to in vitro phosphorylate Escherichia coli-expressed
TR␤-1 (39, 492). Sugawara et al. (492) examined the binding of phosphorylated TR␤-1 to several TREs and found
that phosphorylation selectively enhanced TR homodimer, but not TR/RXR heterodimer, binding to several
different TREs. Bhat et al. (39) showed that phosphorylation enhanced DNA binding by both TR complexes.
Interestingly, phosphorylation by protein kinase A can
decrease v-erbA and chick TR␣-1 monomer binding to
TREs (530). These results suggest that phosphorylation
may be another mechanism, in addition to T3 binding, that
can modulate TR complex binding to TREs. Additionally,
T3 itself can modulate the phosphorylation state of TR
(518).
Recently, Davis et al. (113) have shown that TR␤-1
associates with mitogen-activated protein (MAP) kinase
in coimmunoprecipitation studies and that ligand binding
may stimulate TR phosphorylation by MAP kinase. Interestingly, previous studies have shown that MAP kinase
can modulate transcriptional activity of ER and PPAR␥ by
phosphorylation of the receptor (238, 406). Moreover,
MAP kinase phosphorylation of the steroidogenic factor-1
(SF-1) and ER AF-1 regions leads to enhanced coactivator
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
ies showed that the major endogenous TRAPs are RXRs
or related proteins (287, 420, 494). Third, TR/TRAP and
TR/RXR heterodimer complexes both remained bound to
TREs in the presence of T3 (17, 333, 422, 584, 589) (see
below). Fourth, heterodimer-selective, but not homodimer-selective, mutants were able to mediate transcriptional activation of TRE-containing reporters (21,
140, 344, 592). Mutant TRs containing deletions or amino
acid substitutions of amino acids at positions 290 –310 or
in the ninth heptad region of the LBD concomitantly
decreased heterodimerization and transactivation (21,
140, 344, 360, 592). Fifth, RXR enhanced T3-mediated
transcription in yeast cells that do not contain endogenous TRAPs (65, 187). And last, RXR enhanced T3-mediated transcription in a reconstitutable in vitro transcription system (294).
TR/RXR heterodimer formation increases the repertoire of target genes that can be regulated by T3 as heterodimers bind to TREs with variable sequence and orientation of half-sites (160). Moreover, there are at least
three members of the RXR subfamily, so it is possible that
different RXR isoforms may form TR/RXR heterodimers
that have different TRE-binding specificities and/or abilities to transactivate target genes. Additionally, it is possible that an endogenous ligand like 9-cis-retinoic acid can
bind and activate the heterodimer partner of the TR complex. Of note, addition of both 9-cis-retinoic acid and T3
synergistically activated transcription on two different
TRE-containing reporters (227, 429). However, in other
cases, TR can block 9-cis-binding to RXR and thereby
abrogate retinoid stimulation of target genes (91, 147,
266). Finally, TRs can heterodimerize with other members
of the nuclear receptor family including RAR, PPAR,
chicken ovalbumin upstream promoter transcription factor (COUP-TF), and VDRs (45, 99, 314, 448, 519, 589). The
functional significance of these heterodimers, most of
which have been demonstrated in vitro by EMSA, is not
known. However, they do not appear to be major endogenous TRAPs and may have restricted roles in particular
target genes or tissues (287, 494). If they do have physiological roles, though, these heterodimers increase further the diversity of TR complexes and the potential of
receptor cross-talk on target genes.
Although TRs can form monomers, homodimers, and
heterodimers on TREs in EMSA (284, 583), the role(s) of
TR monomers and homodimers on transcription is not
well understood. In contrast to steroid hormone receptors
in which ligand enhances receptor binding to HREs, T3
decreases TR␣-1 and TR␤-1 homodimer as well as TR␣1/TR␤-1 dimer binding to several TREs arranged as DRs
and IPs (17, 333, 422, 584). Unliganded TR homodimers
also interact better with corepressors than unliganded
TR/RXR heterodimers in vitro (207, 311). Thus it is possible that unliganded homodimers may form a complex
with corepressors that are involved in basal repression of
1107
1108
PAUL M. YEN
VIII. MOLECULAR MECHANISMS OF THYROID
HORMONE RECEPTOR ACTION
A. Corepressors/Basal Repression
In contrast to steroid hormone receptors that are
transcriptionally inactive in the absence of ligand, unli-
ganded TRs bind to TREs and may modulate transcription
of target genes (Fig. 9). Several laboratories showed that
unliganded TRs can repress basal transcription of positively regulated TREs in cotransfection studies (26, 53,
603). It was not known initially whether these observations were physiologically relevant or peculiar to cotransfection systems. Early observations showing that T3 decreased TR homodimer binding to TREs led to the
hypothesis that unliganded TR homo- and/or heterodimers might mediate basal repression (584). This notion was further supported by the demonstration that TR
binding to TREs was important for mediating basal repression, as mutations in TR␤-1 DBD or the TRE primary
sequence abrogated basal repression (26, 592). Unliganded TRs have been shown to interact directly with TFIIB,
a key component of the basal transcription machinery
(25, 183, 394, 520, 523), and potentially can interfere with
the assembly of a functional preinitiation complex at the
promoter. Studies of TR action in in vitro transcription
systems (142) suggested that direct interaction between
TRs and the basal transcriptional machinery could help
mediate ligand-dependent basal repression. On the other
hand, several studies also suggested that soluble corepressors may be critical for mediating basal repression
(407, 522).
The cloning and functional characterization of several corepressors have greatly enhanced our understanding of basal repression and shed light on these previous
issues (Fig. 10). Several laboratories used the yeast twohybrid system or biochemical purification to clone proteins that exhibited decreased interaction with TR and
RAR in the presence of their cognate ligands (83, 211, 295,
442). One of them was a 270-kDa protein called nuclear
FIG. 9. Model for repression, derepression, and transcriptional activation
by TR in the absence or presence of T3.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
recruitment and transcriptional activation (188, 528).
Stimulation of the protein kinase A pathway also potentiated T3-mediated transcription in a cell-specific manner
(301), suggesting multiple kinase pathways may modulate
transcriptional activity of TR. Power et al. (405) have
demonstrated that some nuclear hormone receptors can
be activated by dopamine stimulation in the absence of
ligand, mostly likely via receptor phosphorylation. It is
possible that some ligand-independent effects by TR may
be due to receptor phosphorylation by cell-specific kinases or phosphatases, or due to cell-specific expression
of certain membrane-signaling receptors that can activate
transcription by unliganded TR. In this connection, celltype specific phosphorylation may stabilize TR␤-1 protein
(517). Additionally, it has been shown that DNA binding
by the alternative splice variant of TR␣-1, c-erbA␣-2, is
regulated by casein kinase II phoshorylation of serines in
its carboxy terminus (239). This phosphorylation is critical for determining the dominant negative activity (ability
to block wild-type TR action) by c-erbA␣-2. These findings
suggest that phosphorylation potentially may regulate diverse and important TR functions, although the precise
location of phosphorylation sites, their regulation, and
their functional roles remain to be elucidated.
Volume 81
July 2001
THYROID HORMONE ACTION
1109
FIG. 10. Comparison of the organization and
structure of putative nuclear hormone receptor
corepressors. NCoR, nuclear receptor corepressor.
of the ligand pocket of TR. Differences in the length and
specific sequences of the corepressor and coactivator
interaction sites coupled with the conformational
changes in the AF-2 region upon ligand binding may determine whether corepressor or coactivator binds to TR
(390). Additionally, corepressors can bind to the TR heterodimer partner RXR. It appears that helix 12 of RXR
masks a corepressor binding site in RXR, which is unmasked upon heterodimerization with TR (599).
Recently, several groups have shown that corepressors can complex with other repressors, Sin 3 and histone
deacetylase 1 (HDAC1), that are mammalian homologs of
well-characterized yeast transcriptional repressors RPD1
and RPD3 (13, 200, 271, 347, 352). Thus local histone
deacetylation may play a critical role in basal repression
by nuclear hormone receptors. Moreover, this mechanism
of basal repression may be employed by other transcription factors such as Mad/Max and Myc/Mxi heterodimers
(13, 200, 271). Anti-NCoR antibodies have been shown to
coimmunoprecipitate HDAC activity (200). Additionally,
microinjection of specific antibodies generated against
mSin3 and RPD3 were able to block basal repression by
NCoR (200). Recent studies by Lazar (286) and Wong
(J. M. Wong, personal communication) suggest that
HDAC4 may interact directly with NCoR at a different
repressor site than Sin3 and HDAC1. Recent coimmunoprecipitation studies also suggest that HDAC3 may be the
major HDAC associated with SMRT (286). Another component of the corepressor may be the protooncogene
c-Ski which has been shown to be involved in transcriptional represson by Mad and TR (354). It is likely that
histone deacetylation by unliganded TR/corepressor complex may help maintain local chromatin structure in a
state that shuts down basal transcription. In this connection, studies examining TR␤A promoter in a Xenopus
oocyte system showed that simultaneous chromatin assembly and TR/RXR binding were required for basal repression of transcription (562, 563). This repression was
relieved by addition of T3 and was accompanied by chromatin remodeling. These data demonstrate that histone
acetylation and deacetylation, and the consequent
changes in chromatin stucture and nucleosome positioning, may be important determinants of gene transcription
(Fig. 11). Additionally, DNA methylation may play a role
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
receptor corepressor (NCoR), which also was isolated as
an RXR-interacting protein, RIP 13 (211, 459). It contains
three transferable repression domains and two carboxyterminal ␣-helical interaction domains. NCoR was able to
mediate basal repression by TR and RAR, as well as
orphan members of the nuclear hormone receptor family
such as rev-erbA␣ and COUP-TF. It had little or no interaction with steroid hormone receptors and did not mediate basal repression by these receptors. NCoR also has
been shown to interact with TFIIB, TAFII32, and TAFII70,
so part of its ability to repress transcription may be due to
its ability to interact with the basal transcripitonal machinery. Recently, a truncated version of NCoR, NCoRi,
which is missing the repressor region, has been identified,
which may represent an alternative-splice variant of
NCoR (207). This protein blocks basal repression by
NCoR and potentially may serve as a natural antagonist
for NCoR if it is expressed in signficant amounts in tissues. Another corepressor, SMRT, has been identified and
has homology with NCoR (83, 295, 442). The original
sequence for SMRT was derived from a partial clone, but
it is now appreciated that full-length SMRT is similar in
size and has similar repression and nuclear receptor interaction domains as NCoR. SMRT also is able to mediate
basal repression of TR and RAR in cotransfection studies.
Another protein, small ubiquitious nuclear corepressor
(SUN-CoR), was isolated and enhanced basal repression
by TR and rev-erbA (596). This 16-kDa protein may form
part of a corepressor complex as it interacts with NCoR.
Studies of TR and v-erbA have defined the importance of the hinge region for interactions with NCoR and
SMRT, because mutations in this region abrogate basal
repression without affecting transcriptional activation
(83, 211, 324). Interestingly, rev-erbA␣ contains two amino-terminal regions which interact with NCoR and are
required for basal repression, suggesting that nuclear hormone receptors may have different interaction sites with
corepressors (597). Within the interaction domains of
NCoR and SMRT are consensus LXXI/HIXXXI/L sequences that resemble the LXXLL sequences that enable
coactivators to interact with nuclear hormone receptors
(214, 348, 390). Interestingly, these motifs allow both
corepressors and coactivators to interact with similar
amino acid residues on helices 3, 5, and 6, which are part
1110
PAUL M. YEN
Volume 81
in basal repression as methyl-CpG-binding proteins can
associate with a corepressor complex containing Sin3 and
HDACs (351, 543). This repression was relieved by the
deacetylase inhibitor trichostatin A. These findings suggest that two repression processes, DNA methylation and
histone deacetylation, may be linked via methyl-CpGbinding proteins.
TR also can activate transcription in the absence of
ligand. Samuels and co-workers (201) showed that unliganded TR surprisingly could transactivate via rGH and
PRL TREs in pituitary cell lines (89). Additionally, several
groups have reported ligand-independent gene transcription in neuroblastoma and Xenopus cells (346, 385). It is
not known whether cell-specific activators or inhibitors
or other mechanisms account for these observations.
Last, TRs can activate transcription of negatively regulated genes such as RSV LTR, glycoprotein hormone
␣-subunit, TSH␤, and TRH in the absence of ligand (88,
206, 305, 342, 433). Brent et al. (57) showed that a negative
TRE (nTRE) from the glycoprotein hormone ␣-subnunit
gene could be placed in different positions relative to the
rat growth hormone minimal promoter (even downstream), and still mediate negative regulation. They
showed that the nTRE sequence may play a more important role than its position relative to the minimal promoter. Additionally, several groups have found nTREs
located in the 3⬘-untranslated region of target genes (40,
600). Recent studies have suggested that ligand-independent activation may be mediated by TR recruitment of
corepressors, and this may be mediated by protein-protein interactions of DNA (500, 501). Interestingly, these
effects could be blocked by pharmacological inhibition of
HDAC activity. These findings suggest that histone
deacetylation may promote ligand-independent activation
of a negatively regulated target gene. Another study
showed that T3-mediated negative regulation may also
require HDAC activity (445). On the other hand, NCoRi
(which does not contain the repression domains) enhances ligand-independent regulation in a reporter containing the TRH promoter (207). NCoRi activation function is stronger than NCoR, so the ligand-independent
activation function may map to the carboxy terminus of
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
FIG. 11. Molecular model for basal
repression in the absence of T3 and transcriptional activation in the presence of
T3. X refers to potential unidentified cofactors. See text for details.
July 2001
THYROID HORMONE ACTION
B. Coactivators/Transcriptional Activation
Recent studies using Far-Western and coimmunoprecipitation approaches showed that liganded TR may interact with multiple nuclear proteins that potentially can
form a transcriptionally active complex (141, 394). Work
by several groups previously showed that TRs can interact with general transcription factors (25, 142, 183, 520).
Moreover, these interactions seemed to be ligand dependent, suggesting that direct contact between TR and general transcription factors could play a role in derepression
and transcriptional activation (27, 142). In support of this
possiblity, ER was shown to interact with TBP, TAFII 30,
and TFIIB (217, 221, 434), and PR could interact with
TAFII 110. Petty et al. (396) also showed that liganded
TR␤ interacts with several Drosophila TAFs, particularly
TAFII 60 and TAFII 110, and the latter could augment
T3-dependent transcription (396).
Previous studies using cotransfection and in vitro
transcription systems highlighted the importance of minimal promoters in mediating T3-regulated transcription
(129, 491, 580). These studies raised the possibility that
adapter proteins, or coactivators, might bridge the liganded TR complex with components of the basal transcriptional machinery. Previously, several viral transcription
factors were shown to interact with coactivators to enhance transcription (62, 170, 310). Similarly, several potential coactivators for hormone-regulated transcription
were reported, including CREB binding protein (CBP)
which interacts with CREB (269). Also, several groups
identified proteins that interacted with ER in a liganddependent manner and thus could potentially participate
in estrogen-dependent transcriptional activation (72, 186,
221). These putative coactivators interacted with the AF-2
region located in helix 12 of the LBD. This region has high
homology among many members of the nuclear hormone
receptor family and was shown to be important for liganddependent transcription for several receptors (27, 31, 105,
278, 601) (Fig. 6). This region contains a critical ␾␾XE␾␾
sequence in which ␾ represents a hydrophobic amino
acid and X represents any amino acid.
Recently, O’Malley and co-workers (369) used a yeast
two-hybrid system to clone a putative factor that enhanced transcriptional activation for steroid hormone receptors, which they called steroid receptor coactivator-1
(SRC-1) (Fig. 12). This protein also associates with several other members of the nuclear hormone receptor
superfamily, including TRs, and enhances their liganddependent transcription. Subsequent work has shown
that the original cDNA clone was only partial, and the
full-length clone encoded a 160-kDa protein (235, 369,
507). Additionally, there may be alternative splicing of
SRC-1 mRNA, leading to multiple SRC-1 isoforms. The
functional significance of the SRC-1 isoforms currently is
not known; however, one splice variant, SRC-1E, which
lacked 56 amino acids of SRC-1 and had unique 14 amino
acids at the carboxy terminus, enhanced T3-mediated
transcriptional activation better than SRC-1 (194, 235).
Another 160-kDa protein, TIFII/GRIP-1/SRC-2, has been
identified that interacts with liganded nuclear hormone
receptors, including TRs, and has partial sequence homology with SRC-1. These findings suggest there may be a
family of coactivators related to SRC-1 (210, 541). Indeed,
another family member, AIB1/pCIP/ACTR/TRAM1/RAC3/
SRC-3, has been identified that augments transcription by
nuclear hormone receptors (19, 82, 306, 503, 526). As seen
in Figure 12, there are several common features among
these putative coactivators. First, there are multiple putative nuclear hormone receptor interaction sites that
seem to bear a signature LXXLL sequence motif in which
X represents any amino acid. This sequence has been
shown to be important for coactivator binding to nuclear
hormone receptors (199, 325). These coactivators also
have a polyglutamine region, similar to androgen recep-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
NCoR (93). These studies suggest a role for corepressors
in ligand-independent activation of some negatively regulated target genes, but the precise mechanism needs to be
further defined.
The physiological role of corepressors is only partially understood. Corepressors have been implicated in
leukemias that have RAR fusions and acute myolegenous
leukemia/eight-twenty-one (ETO) fusions from chromosomal translocations (158, 176). Additionally, the TR␣/
TR␤ double-knockout mice have a milder phenotype than
congenitally hypothyroid mice, suggesting that basal repression by unliganded receptor may have more deleterious effects on transcription in target tissues. Lazar (286)
recently found that transducin B-like protein coimmunoprecipitated with SMRT. This histone-binding protein was
deleted in patients with congenital sensory-neural deafness (33). Interestingly, TR␤ knockout mice and affected
patients from a family with resistance to TH due to absence of TR␤ also have sensory neural deafness (149,
414). It is interesting to speculate that absence of TR␤ or
an associated repressor complex protein can cause a
similar phenotype. Last, Feng et al. (135) have targeted a
dominant negative NCoRi to the liver in transgenic mice.
They observed that basal transcription of spot 14 and Bcl3
(a target gene identified by cDNA microarray) was higher
in hypothyroid transgenic mice than in littermate controls. When mice were treated with T3, both genes were
induced to similar levels. These findings suggest that
NCoR-mediated basal repression in vivo could be reversed by overexpression of NCoRi without effects on
transcriptional activation. Interestingly, transcription of
several other target genes was unchanged in hypothyroid
transgenic mice, suggesting that there may be gene-specific repression by different corepressors.
1111
1112
PAUL M. YEN
12. Comparison of the organization and structure of p160 nuclear hormone receptor coactivators.
tors. There is polymorphism observed in the length of
these trinucleotide repeats of SRC-3, but the functional
signficance, if any, is not known (198). Additionally, in the
amino-terminal region, there is a basic helix-loop-helix
(bHLH) motif, suggesting that these coactivators may
bind to DNA. Also located in this region is the so-called
Per-Arnt-Sim (PAS) domain, which interestingly, also is
seen in several transcription factors that regulate the
circadian rhythm and in the heterodimer partner of the
dioxin receptor (387, 402). Thus the PAS region may serve
as a dimerization interface and potentially allow crosstalk among other coactivators or transcription factors.
SRC-1 can be phosphorylated by MAP kinase, and its
activity may be regulated by membrane-bound receptors
such as epidermal growth factor (431). There also are
multiple nuclear receptor interaction domains in the
SRCs that may confer receptor specificity (122, 316, 505,
540). Among the SRC family members, there may be a
certain degree of functional redundancy, as SRC-1 knockout mice were viable and fertile and had only a modest
decrease in growth and development in reproductive tissues and a mild disurbance of the hypothlamic/pituitary/
thyroid (HPT) axis (550, 570). Interestingly, there was a
concomitant increase in TIF2/SRC-2 mRNA in these mice,
suggesting that upregulation of TIF2 may compensate for
some of the loss of SRC-1 function. Interestingly, the
SRC-3 knockout mouse has a much more severe phenotype with decreased growth, delayed puberty, and decreased litter size (569). The effects on the HPT axis and
potential contribution to the phenotype are not known at
the present time.
Recently, several groups have shown that SRC-1 can
interact with the CBP, the putative coactivator for cAMPstimulated transcription as well as the related protein,
p300, which interacts with the viral coactivator E1A (73,
235, 476, 577). CBP/p300 can serve as a coactivator for
CREB, p53, AP-1, and NFkB. It is possible that CBP/p300
may serve as an integrator molecule for different signaling
inputs (262) (Fig. 10). The biological importance of CBP
in humans is exemplified by patients with RubensteinTaybi syndrome who have mental retardation, short stature, and craniofacial and other anomalies, as well as
mutations in CBP (393). p300 knockout mice die in utero
and display defects in cell proliferation as well as neural
and heart development (578). CBP knockout mice also die
in utero with defects in hematopoesis and angiogenesis
(363). These findings suggest that although CBP and p300
behave similarly in enhancing nuclear hormone receptor
action in cotransfection studies, they are not functionally
equivalent in vivo.
Recent studies also have shown that CBP/p300 can
interact with PCAF (p300/CBP-associated factor), the
mammalian homolog of a yeast transcriptional activator,
general control nonrepressed protein 5, GCN5 (42, 574).
Like GCN5, PCAF has intrinisic histone acetyltransferase
(HAT) activity. The HAT activity of PCAF is directed
primarily toward H3 and H4 histones. PCAF itself is part
of a preformed complex that contains TBP associated
factors (TAFs) which have been shown to interact with
SRC-1 and SRC-3 (82, 361, 479). CBP also has been shown
to be part of a stable complex with RNA polymerase (pol)
II (350). Thus PCAF and CBP can serve as adaptors of
nuclear receptors to the basal transcriptional machinery
and have an enzymatic function (HAT activity). These
dual roles likely contribute to nuclear receptor transcriptional activity (Fig. 12). Subsequent studies showed that
CBP/p300, as well as SRC-1 and SRC-3, have HAT activity,
although their specificity for histone substrates differed
(82, 262, 362, 479). Recruitment of different coactivators
with different HAT activities may be a mechanism for
promoter- or cell-specific regulation of target genes.
Recently, Lanz et al. (277) reported that an RNA
transcript, steroid receptor RNA activator (SRA), could
enhance AF-1-mediated transcription of the progesterone
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
FIG.
Volume 81
July 2001
THYROID HORMONE ACTION
for nuclear hormone receptors; however, the precise
functional roles of the two different coactivator complexes are not known. It is possible that the p160/SRC
complex may initiate transcriptional activity by recruiting
cofactors with HAT activity to ligand-bound nuclear hormone receptors, and DRIP/TRAP complex may then bind
to nuclear receptors that can then recruit RNA Pol II
holoenzyme to promote transcription of target genes (Fig.
11). Recently, it has been shown that CBP can acetylate
ACTR (SRC-3) and promote its dissociation from nuclear
hormone receptors, so acetylation of components of the
p160/SRC complex from HAT activity may facilitate the
exchange of complexes (82). Balasubramanian and Moore
(22) recently showed that mammalian homologs of Sw-1/
Snf, BRG-1 and BRM-1, can associate with TR in vitro and
activate transcription. These chromatin remodeling proteins have ATPase activity and previously were shown to
enhance GR-mediated transcriptional activity in yeast
(67). Recently, the sequential recruitment of coactivator
complexes and correlation with transcription has been
demonstrated for ER and TR (461a, 461b). Understanding
the interplay of these coactivator complexes and the
mechanisms by which they activate transcription will certainly be the subjects of intense study in the future.
In addition to the p160/SRC and DRIP/TRAP complexes, a number of coacativators have been identified,
but their relationship to these complexes, if any, is not
known. Moore and co-workers (295, 296) have identified
several other proteins that interact with TR␤-1 LBD.
These proteins, called TRIPs (TR-interacting proteins),
are diverse; one of them is the human homolog of a yeast
transcription factor, another a new member of a class of
nonhistone chromosomal proteins, and yet another contains a conserved domain asssociated with ubiquitination
of specific target proteins. Monden et al. (334) have identified a putative coactivator, p120, that does not bear
homology with SRC-1 but interacts with liganded TR and
contains an LXXLL motif (334). Another protein called
TRIP230 (TR and Rb interacting protein of 230 kDa) was
intially cloned on the basis of its ability to interact with
the retinoblastoma protein (74). This protein binds to
liganded TR and augments T3-mediated transcriptional
activation. Interestingly, cotransfection of Rb blocks the
TRIP230 enhancement of transcription, suggesting crosstalk between TR- and Rb-mediated pathways. Another
coactivator, TR-binding protein (TRBP; ASC-2; RAP250),
interacts with TR via a LXXLL motif and stimulates transcription of several nuclear hormone receptors, AP-1,
CREB, and NF␬B (66, 252, 298). It also interacts with
DRIP 130 and CBP/p300. Yet another protein, TR uncoupling protein (TRUP), binds to TR/RXR heterodimers and
prevents their binding to TREs (64). In contrast to coactivators, it blocks T3-mediated transcription, presumably
by the foregoing mechanism. Additionally, there are a
number of other nuclear proteins that have been identi-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
receptor and was part of the SRC-1 complex (277). It is
possible that SRA may be part of a ribonucleoprotein
scaffold that many help recruit SRC-1 to nuclear hormone
receptors. Additionally, Stallcup recently showed that a
methyltransferase, CARM-1, can be associated with
GRIP-1 and methylate the histone H3 (81). These findings
suggest that histone methylation as well as acetylation
may be employed to alter local chromatin stucture.
In vivo foot-printing studies also have suggested conformational changes in the chromatin structure near
TREs and retinoic acid response elements after ligand
addition (118, 143, 243, 562). Additionally, liganded receptor binding to the hormone response element allowed
other enhancer elements in the promoter to be footprinted (118). In studies on TR␤A promoter in Xenopus
oocytes, Wolffe et al. (561, 562) have shown that chromatin assembly is critical for basal repression by unliganded
TR/RXR heterodimers. Moreover, trichostatin A, a HDAC
inhibitor, relieves this basal repression but does not disrupt chromatin structure. In contrast, liganded TR/RXR
disrupts chromatin structure, releases the corepressor
complex, and recruits coactivators such as CBP and
PCAF with HAT activity. Recent studies with green fluorescent proteins have shown that TRs are predominantly
in the nucleus and that T3 can mediate intranuclear reorganization in the presence of ligand (34). Moreover, this
change does not require DNA binding. This reorganization
may be due to association with chromatin, active transcriptional complexes, and/or nuclear matrix components
(34, 213, 482).
Recently, the groups of Freedman (411, 412) and
Roeder (595) have isolated a complex of proteins (DRIPS,
vitamin D receptor interacting proteins; TRAPs, TR-associated proteins) ranging from 70 to 230 kDa that interacted with liganded VDRs and TRs in GST-pulldown studies. These proteins had similar sizes as a previously
reported complex of proteins originally isolated by coimmunoprecipation with an antibody against epitope-tagged
TR␣. A critical coactivator in this complex is DRIP205/
TRAP220, which contains a LXXLL motif similar to SRC
family members and appears to anchor ⬃15 other proteins. Interestingly, none of these proteins is a member of
the SRC family and their associated proteins. Instead,
several DRIP/TRAP components are mammalian homologs of the yeast Mediator complex, which associates
with RNA Pol II (179, 219). DRIP/TRAP complex is virtually identical to a previously described SRB-MED-containing cofactor complex (SMCC) that can interact with p53
and VP16 to enhance transcription (219). These findings
suggest that TR may recruit DRIP/TRAP complex which,
in turn, may recruit or stabilize RNA Pol II holoenzyme by
virtue of shared subunits. Additionally, DRIP/TRAP complex does not appear to have intrinisic HAT activity (411).
Taken together, these findings suggest a model in which
there may be at least two distinct coactivator complexes
1113
1114
PAUL M. YEN
fied by two-hybrid screening that interact with steroid
hormone receptors and also may interact with TRs (212,
326). These findings suggest that there may be different
classes of coactivators in addition to the SRC and DRIP/
TRAP complexes. However, the functional significance of
these coactivators on TR-mediated transcription remains
to be further defined.
C. Cross-talk With Other Nuclear
Hormone Receptors
with ER may be an important modulator of estrogen
response in this neuroendocrine tissue.
ERs also can block T3-regulated transcription by TR
(579, 591). The mechanism for transcriptional blockade
may depend on the TREs of particular target genes. In one
example, ER␣ blocked the T3-mediated negative regulation of the glycoprotein hormone ␣-subunit gene (579).
ER bound to a hormone response element containing an
imperfect palindrome sequence. TR monomer also bound
to this composite response element and negatively regulated transcription. Thus ER competition with TR for
DNA binding to the response element may block T3-mediated negative regulation of this target gene. Additionally, ER blocked T3-mediated transcriptional activation
via DR4 and F2 (591). In contrast to the glycoprotein
hormone ␣-subunit gene, this blockade did not require
DNA binding since the transcriptional blockade was observed with ER mutants that did not bind to TREs or
EREs. Similar results also were observed using GR and
GR truncation mutants. Interestingly, neither ER or GR
had any effect on repression of basal transcription by
unliganded TR, suggesting that this blockade by the steroid hormone receptors had a selective effect on these
two TR functions. It is likely that overexpression of ER
and GR titrated limiting amounts of a cofactor(s) critical
for transcriptional activation by liganded TR, but not
basal repression, by unliganded TR. Similar results were
observed for PR- and TR-mediated transcription in an in
vitro transcription system (601). There also are several
other examples of cross-talk between other nuclear hormone receptors and TRs. PPARs can decrease T3-mediated transcription, possibly via competition for binding to
HREs and/or titration of RXRs or coactivators (45, 233,
332). COUP-TF also can interfere with TR-mediated as
well as RAR- and VDR-mediated transcriptional activity
(99).
Nuclear hormone receptors have been shown to have
cross-talk with c-jun and c-fos protooncogene (AP-1) proteins (450). On the proliferin promoter, positive or negative glucocorticoid regulation was regulated by c-jun or
c-fos and binding to a composite element containing overlapping an AP-1 binding site and glucocorticoid response
element (119). In other cases, c-jun and GR have reciprocal antagonism mediated via protein-protein interactions (451, 576). Similarly, several groups have shown a
ligand-dependent repression of AP-1 activity by TRs (312,
388, 604). Interestingly, Lopez et al. (312) also have shown
that unliganded TR can positively regulate AP-1 activity
on some elements (312). Additionally, c-jun can antagonize T3-mediated transcription via positively and negatively regulated TREs (312, 388, 560, 604). The mechanism
for these reciprocal effects seems to be protein-protein
interactions between TR and c-jun because several
groups have observed formation of TR/c-jun complexes in
solution (312, 560, 604). Furthermore, TR and AP-1 com-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
TRs and other nuclear hormone receptors can modulate transcriptional activities of each other. This crosstalk can occur via several mechanisms: promiscuous
binding to HREs, formation of heterodimers, and competition for cofactors (450, 582). The first two mechanisms
seem to be the most prevalent among nuclear hormone
receptors and can result in either enhanced or decreased
transcriptional activity. As mentioned earlier, TR/RXR
heterodimers may mediate dual-ligand regulation of transcription in some instances and block ligand-dependent
transcription via RXR in others (162, 297, 314, 429, 493).
Similar mechanisms also may occur for TR blockade of
RAR-mediated transcription (29, 297, 589).
Carlberg and co-workers (448) demonstrated that
VDR and TR formed heterodimers on the mouse and rat
calbindin HREs which are arranged as DR3 and DR4,
respectively, and both vitamin D and T3 could coregulate
transcription via these elements. VDR/RXR, but not VDR/
TR, bound to several TREs, and VDR exhibited dominant
negative activity as it blocked T3-mediated transcriptional
activity on DR4 and the chick lysozyme TRE, F2 (587).
Aranda and co-workers (156) also have found that VDR
blocked TR-mediated transcription in the rGH TRE. Interestingly, cotransfection of SRC-1 or SRC-3 could augment
VDR-mediated transcription on TRE- and RARE-containing reporters (DR4 and DR5) (504).
TRs and ERs also exhibit cross-talk. TRs and ERs
have identical “P box” sequences and recognize the same
consensus half-site sequence, AGGTCA (160). However,
ERs bind as homodimers to EREs arranged as palindromes separated by three nucleotides. Although TRs can
bind to estrogen response elements (EREs), they are
unable to transactivate via these elements (420, 456).
Nonetheless, TRs can block estrogen stimulation of vitellogenin gene expression possibly by forming transcriptionally inactive complexes (e.g., TR/RXR heterodimers)
on the ERE (161, 456, 609). Zhu and co-workers (397, 608)
have shown that TR can bind to the EREs of pro-enkephalin and progesterone receptor promoters in rat hypothalamic cells and decrease estrogen-mediated proenkephalin mRNA synthesis. Because these two estrogenregulated target genes are important in the hypothalamic
regulation of sexual behavior in rats, coexpression of TR
Volume 81
July 2001
THYROID HORMONE ACTION
plexes can both interact with CBP, providing another
potential point for cross-talk. Recently, Yamamoto and
co-workers (426) examined TR- and GR-mediated repression of collagenase gene transcription by jun. Interestingly, two jun mutants disrupted TR-mediated repression
but not GR-mediated repression. Also, the repression by
TR, but not GR, could be blocked by the histone deacetylase inhibitor trichostatin A. These findings suggest that
TR- and GR-mediated repression on this gene occur via
distinct mechanisms.
D. Nongenomic Effects of TH
a variety of tissues via a mechanism that does not require
new protein synthesis, suggesting a direct effect on the
plasma membrane transport system (453– 455). Additionally, T3 has been shown to bind to an endoplasmic reticulum-associated protein, prolyl hydroxylase, and also to a
subunit of pyruvate kinase when the enzyme is monomeric but not tetrameric (20, 85, 237). It is not known
whether T3 modulates the activities of these enzymes or
whether these enzymes may subserve other functions
related to T3 action such as transport or storage. In this
connection, it is of interest that thyroxine, T4, can inhibit
deiodinase type II activity by an allosteric mechanism and
may promote targeting of a substrate-binding subunit to
endosomes (132). Recently, Stensapir et al. (481) also
have shown that deiodinase type II can be proteosomally
degraded in the presence of T4 and/or T3.
Sterling and colleagues (483– 485) reported the presence of specific mitochondrial receptors over 20 years ago
and thus provided an attractive unifying model for T3
effects on mitochondrial activity and cellular energy state.
There is some evidence that the site of TH action in
mitochondria is the adenine nucleotide translocase of the
inner mitochondrial membrane (428, 483). However, this
work has been difficult to confirm as there are conflicting
reports in the literature on the site of TH action in mitochondria (116, 185, 276). Recently, a 43-kDa protein related to TR␣-1 LBD has been described in mitochondria
that also could bind to TREs and mitochondrial DNA
sequences (70, 567). Moreover, transfection of TR␣-1 in
CV-1 cells resulted in mitochondrial localization and stimulation of mitochondrial activity. These results suggest
that there indeed may be specific mitochondrial receptors
for T3 which also may serve as transcription factors in
mitochondria.
There also are reports of nongenomic effects on cell
structure proteins by THs. Actin depolymerization blocks
type II deiodinase inactivation by T4 in cAMP-stimulated
glial cells, suggesting that an intact actin cytoskeleton is
important for this downregulation of deiodinase activity
(131, 132). Interestingly, T4, but not T3, can promote actin
polymerization in astrocytes (468) and thus may influence
the downregulation of type II deiodinase activity by a
secondary mechanism, perhaps by targeting to lysosomes
(131, 132). Moreover, the regulation of actin polymerization also could contribute to the effects of TH on arborization, axonal transport, and cell-cell contacts during brain
development. In this connection, Farwell et al. (133) have
shown that T4 was required for integrin clustering and
attachment to laminin by integrin in astrocytes.
Finally, Davis and co-workers (307) have observed
that the antiviral effects of interferon-␥ can be potentiated
by T4 and T3. These effects were rapid and did not require
protein synthesis because they were not blocked by cycloheximide treatment and required protein kinase C and
protein kinase A activation. These data suggest that cir-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
There is general agreement that most of the effects of
T3 are mediated by TR regulation of target gene transcription in the nucleus. However, there are a number of
reports on nongenomic effects by T3 and T4 (116). Evidence for these nongenomic effects include the lack of
dependence on nuclear TRs and structure-function relationships of TH analogs that are different from their affinities for TRs. There also can be rapid onset of action
(typically seconds to minutes), and utilization of membrane-signaling pathways, typically involving kinases or
calmodulin, that have not been implicated in direct TR
function. The putative nongenomic effects by TH are
diverse. However, the biological significance is not well
understood in many cases.
Transport of T3 across plasma and nuclear membranes have been subjects of interest over the years. T3 is
lipophilic and generally thought to diffuse passively
across the plasma and nuclear membranes. However,
there is some evidence for facilitated transport across
plasma membranes and high-affinity TH binding sites in
the plasma membranes of different cells (274, 335, 378,
421, 439). In one study of human erythrocytes, T3 is
concentrated 55-fold inside cells. There also is evidence
for a stereo-specific transporter of T3 into the nucleus as
there was a 58-fold higher concentration of L-T3 and 4-fold
higher concentration of D-T3 in the nucleus than in the
cytoplasm using isotope dilution methods, although different affinities for TR may also contribute to this difference (378). However, the identification of the specific
proteins that might be involved in T3 transport has remained elusive. One potential transporter may be the
multidrug resistance P-glycoprotein that can modulate TH
concentration when overexpressed in cells (421). Another
family of transporters may be the organic anion transporter proteins that have been shown to import TH into
hepatocytes (1, 154).
In addition to transporters, some other potential targets of T3 in the plasma membrane include Ca2⫹-ATPase,
adenylate cyclase, and glucose transporters (112, 115,
274, 335, 378, 439, 454, 455). In the last case, it has been
long appreciated that T3 can enhance uptake of sugars in
1115
1116
PAUL M. YEN
culating levels of T4 may play an important role in modulating cytokine effects in early host defense.
IX. THYROID HORMONE EFFECTS
ON TARGET ISSUES
A. Bone
TH is critical for normal bone growth and development. In children, hypothyroidism can cause short stature
and delayed closure of the epiphyses. Biochemical studies
have shown that TH can affect the expression of various
bone markers in serum, reflecting changes in both bone
formation and resorption (10, 337, 430). TH increases
alkaline phosphatase and osteocalcin in osteoblasts. Additionally, osteoclast markers such as urinary hydroxyproline, urinary pyridinium, and deoxypyridinium
cross-links are increased in hyperthyroid patients. These
observations suggest that both osteoblast and osteoclast
activities are stimulated by TH. Indeed, there is enhanced
calcification and bone formation coupled to increased
bone resorption in hyperthyroid patients (328, 337). Additionally, the time interval between formation and subsequent mineralization of osteoid is shortened. The net
effect on these bone cells is bone resorption and loss of
trabecular bone thickness in hyperthyroidism. There also
is marked increase in porosity and decreased cortical
thickness in cortical bone in hyperthyroid patients (30,
175, 328, 430). These effects can lead to osteoporosis and
increased fractures.
TH may act on bone via TH stimulation of growth
hormone and insulin-like growth factor I (IGF-I) or by
direct effects on target genes. Mundy et al. (339) demonstrated that T3 had a direct effect on bone resorption in
organ culture, suggesting the latter mechanism could occur. Recent studies have shown that T3 also can directly
stimulate IGF-I production in osteoblasts and enhance T3
stimulation of [3H]proline incorporation, alkaline phosphatase, and osteocalcin (215). TRs recently have been
demonstrated in osteoblast cell lines, osteoclasts derived
from an ostoclastoma, as well as in rat and human bone
samples (5, 6, 12, 329, 554). Both TR␣-1 and TR␤-1 as well
as c-erbA␣-2 are expressed in most osteoblast cell lines,
although there is a predominance of TR␣-1 in some cell
lines (e.g., ROS25/1 and UMR 106) (554). Williams et al.
(554) have speculated that osteoblast phenotype expression may correlate with specific TR isoform expression as
the more undifferentiated cell lines expressed predominantly TR␣-1. TR␤-1 and c-erbA␣-2 are highly expressed
in chondrocytes (5). Moreover, TH inhibits growth and
stimulates differentiation of chondrocytes in culture
(218). Recent studies have shown that TR␤2 mRNA was
unexpectedly expressed in human chondrocytes and osteoclasts in situ (6).
Little is known about direct TH effects on osteoclasts
because of the difficulty in obtaining primary cultures or
cell lines. Recently, TR protein was detected in a human
osteoclastoma and in human bone samples by immunostaining (5, 12), suggesting that TH might have direct
effects on osteoclasts. However, two groups have used a
bone slice resorption assay to show that functionally
isolated osteoclasts were unable to respond directly to T3
by increasing bone resorption, and could only do so if
other bone cells were present (9, 58). These results would
suggest that TH may not have a direct effect on bone
resorption but may mediate its effects via paracrine factors secreted by osteoblast cells. Indeed, TH stimulated
prostaglandins and IGF-I in organ culture studies (247).
Additionally, there have been reports of interferon-␥ and
cyclosporin A inhibiting bone resorption by TH, suggesting cytokines may also serve as mediators of TH effects
on osteoclasts (247, 273). Additionally, a clinical study
suggests that interleukin-6 may be involved in mediating
bone loss in hyperthyroidism (272).
Although TH increases the activities of osteoblasts
and osteoclasts in vivo and in culture, little is known
about its effects on the transcription of target genes in
these cells. There are a number of osteoblast proteins that
are stimulated by TH. These include proteins involved in
matrix formation such as alkaline phosphatase, osteocalcin, and collagen (10, 247). Additionally, IGF-I and IGFbinding protein-2 mRNA are stimulated by T3 in rat primary cultures and osteoblastic cell lines (247). However,
it is not known whether TH directly regulates transcription of these target genes. Varga and co-workers (163)
have used subtractive hybridization of TH-treated mouse
osteoblastic cells to isolate a cDNA that corresponded to
the insulin growth factor binding protein-4 (IGFBP-4)
(163). IGFBP-4 mRNA was stimulated by T3 and retinoic
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
TRs are expressed in virtually all tissues, although
the relative expression of TR isoforms may vary among
tissues (128, 204, 487). As mentioned previously, TR␤-1
mRNA is highly expressed in liver but also expressed in
almost all other tissues, whereas TR␤-2 mRNA is most
highly expressed in the anterior pituitary. TR␣-1 is expressed in almost all tissues. In addition to this variable
expression of TR isoforms in different tissues, the role of
TH can vary in different tissues. Indeed, the myriad effects by a single hormone on so many different tissues is
surprising and underscores TH’s vital role in cellular function. Thus, in addition to its role on the metabolism of
macronutrients and overall energy and oxygen consumption, TH also regulates important functions in specific
tissues. Recently, the transcriptional regulation of target
genes in some of these tissues has been studied. We
highlight some of the effects of TH in its major target
tissues, and if known, describe their effects on the transcription of target genes in those tissues.
Volume 81
July 2001
THYROID HORMONE ACTION
acid in mouse osteoblastic cells after 48 h of treatment
and remained elevated after 14 days of treatment. The T3
stimulation of IGF and IGFBPs suggests that TH may
participate in osteoblast differentiation and proliferation
by regulating growth factor synthesis and action. As mentioned earlier, little is known about the direct role of T3 on
osteoclasts. Thus far, no T3-regulated target genes have
been described in osteoclasts.
B. Heart
There is no change in ␣-MHC mRNA level in the atria. This
developmental switch in the rat ventricles likely is triggered by the surge in circulating TH levels that occurs just
after birth. It should be noted that in humans and higher
mammals, there is a different developmental pattern as
myosin V3 (␤/␤) is predominantly expressed in the ventricles from fetal development to adulthood, whereas V1
(␣/␣) is expressed in the atria. Additionally, the effects of
T3 on induction of ␣-MHC mRNA and protein have been
small in higher mammals, suggesting that other factors in
addition to a switch in MHC isoforms may be playing a
role in the inotropic action of TH in these species compared with rodents and rabbits. However, in one clinical
study, a man with profound hypothyroidism and severe
cardiomyopathy underwent serial ventricular biopsies before and after T4 replacement (270). The patient’s ventricular sample showed a low ␣-MHC mRNA level before
treatment that increased 11-fold after T4 treatment. The
patient had significant improvement in several indices of
cardiac function, suggesting that induction of ␣-MHC by
TH likely contributed to his clinical outcome.
The promoter and upstream regions of ␣- and ␤-MHC
genes have been analyzed, and putative TREs for both
these genes have been reported (336). In the ␣-MHC
promoter there are two TREs that are imperfect direct
repeats separated by four nucleotides located between
⫺100 and ⫺150. In vitro binding studies and cotransfection studies suggested that the upstream TRE may be
more important for T3-mediated transcription. However,
transgenic studies in which the transgene contained the
␣-MHC promoter linked to the chloramphenicol acetyltransferase (CAT) cDNA showed that mutation of the
downstream, rather than the upstream TRE, reduced CAT
activity in the atria and ventricles of euthyroid mice (490).
␤-MHC is negatively regulated by T3 (364). A putative TRE
containing a single half-site that is located adjacent to the
TATA box may play a role in this negative regulation
(138).
The rate of diastolic relaxation of the heart is related
to intracellular Ca2⫹ concentration and sarcoplasmic reticulum Ca2⫹-ATPase (SERCA2) activity. The ATPase is
an ion pump that removes calcium from the cytosol and
stores it in the sarcoplasmic reticulum during diastole.
This decrease in the intracellular Ca2⫹ generated during
systole then leads to muscle relaxation. Hypothyroid rats
had decreased levels of SERCA2 mRNA that could be
markedly stimulated by T3 administration (427). Similar
findings also were observed in fetal chicken cardiac myocytes (598). These findings suggest that induction of this
ATPase may account for TH enhancement of cardiac
output by relaxing the heart with greater speed (lusitropic
effect). Three different TREs that are arranged as DRs
and IPs in the promoter region of the SERCA2 gene that
confer T3 responsiveness (191, 471). T3 also has been
shown to regulate expression of several ion channels in
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
TH lowers systemic vascular resistance, increases
blood volume, and has inotropic and chronotropic effects
on cardiac function (248). The combination of these effects on both the circulation and the heart itself results in
increased cardiac output. Hyperthyroid patients have a
high output circulation state, whereas hypothyroid patients have low cardiac output, decreased stroke volume,
decreased vascular volume, and increased systemic vascular resistance (248). These changes in cardiac function
by TH ultimately depend on the regulation of target genes
within the heart and indirect effects due to hemodynamic
changes by TH.
TH enhances overall total protein synthesis in the
heart (120, 121). Additionally, it regulates the transcription of several specific proteins that are critical for cardiac function such as myosin heavy chain (MHC) genes
(120). The myosin holoenzyme has a molecular mass of
500,000 kDa and is composed of two MHCs and four light
chains. There are two heavy myosin genes (␣ and ␤)
whose products dimerize to form three different myosin
chain isoenzymes: myosin V1 (␣/␣), myosin V2 (␣/␤), and
myosin V3 (␤/␤). The relative expression of the MHC
genes in ventricles is species dependent, since ␣-MHC
gene is highly expressed in rodents and rabbits, whereas
␤-MHC gene is predominantly expressed in humans. Myosin V1 has higher ATPase activity and increased velocity
of fiber shortening than myosin V3, so the relative expression of isoenzymes in the heart can determine cardiac
contractility. In hypothyroid rats, myosin V3 predominates so the less active myosin subtype participates in the
contractile process resulting in decreased velocity of fiber
shortening. In contrast, T3 treatment stimulates ␣-MHC
gene expression and decreases ␤-MHC gene expression,
leading to increased myosin V1, and enhanced cardiac
contractility. These opposing effects on MHC gene expression have been demonstrated in whole animals as
well as neonatal rat myocytes in culture (23, 120, 336).
TH also regulates myosin isoenzyme expression during development (336). In the rat fetus, ␣-MHC mRNA
expression is high in the atria, whereas ␤-MHC mRNA
expression is high in the ventricles. ␣-MHC mRNA then
increases shortly after birth in the ventricles and almost
completely replaces ␤-MHC mRNA 7 days after birth.
1117
1118
PAUL M. YEN
C. Fat
TH plays important roles in the development and
function of brown and white adipose tissue (8). TH can
induce white adipose tissue (WAT) differentiation from
preadipocytes in young rats as well as in preadipocyte cell
lines such as Ob17 and NIH3T3-F442A cells (139, 177, 303,
514). In these studies, T3 not only induced intracellular
lipid accumulation and various adipocyte-specific markers such as malic enzyme and glycerophosphate dehydrogenase, but also stimulated adipocyte cell proliferation
and fat cell cluster formation (139, 177).
The mechanism(s) by which T3 induces WAT differentation currently is not known but likely involves transcriptional regulation of important target genes by TRs.
Both TR␣-1 and TR␤-1 are expressed in Ob17 cells, with
the TR␣-1 as the predominantly expressed TR isoform.
Rev-erbA␣ also is induced during the differentiation of
NIH3T3-L1 fibroblasts into adipocytes (80). This induction
of rev-erbA␣ was related to an increase in TR␣-1/cerbA␣-2 levels. Additionally, enzymes of the lipogenic
pathway, ATP-citrate lyase, malic enzyme, and fatty acid
synthase, are induced by T3 in differentiating adipocytes
(43, 159, 245, 389), suggesting T3 promotes the acquisition
of differentiated functions in white adipocyte tissue.
Studies in the adult rat have shown that T3 plays
important roles in regulating basal oxygen consumption,
fat stores, lipogenesis, and lipolysis (374, 375). In WAT, T3
induces key lipogenic enzymes such as acetyl CoA carboxylase, malic enzyme, glucose-6-phosphate dehydrogenase, fatty acid synthase, and spot 14 (43, 159, 245, 338,
389). The expression of these genes is also modulated by
other factors such as high-carbohydrate diet, insulin, and
cAMP (374, 375). Additionally, T3 also regulates lipolysis
in a coordinate manner with lipogenesis (374, 404). Recently, a member of the nuclear hormone receptor family,
PPAR␥, has been shown to stimulate differentiation of
adipocytes (527). Although prostaglandin J2 and thiazolidinediones are the major ligands for PPAR␥, fatty acids
have been shown to stimulate transcriptional activity of
PPARs, either by metabolites or by induction of genes
that may promote formation of endogenous ligands
within the cell (146, 251, 527). Thus TH stimulation of
lipolysis may activate other nuclear hormone receptor
systems, and thereby promote differentiation.
Recent studies also have shown that both TR␣ and
TR␤-1 are differentially expressed during the development of brown adipose tissue (BAT) (529), a major contributor to facultative thermogenesis in rodents. Facultative thermogenesis occurs in response to cold exposure
or overeating and depends on T3 and adrenergic stimulation of mitochondrial uncoupling protein (UCP) synthesis
(164, 203, 375, 432). There are three UCP isoforms, UCP1,
UCP2, and UCP3, that are stimulated by T3 in rat BAT (49,
279, 359, 408). UCP3 mRNA is stimulated by T3 in mouse
BAT and skeletal muscle (168, 226). It is not known
whether these effects are directly mediated by T3 or via
downstream signals such as free fatty acids generated by
lipolysis. The stimulation of UCP synthesis increases thermogenesis by uncoupling oxidative phosphorylation resulting in energy dissipation as heat. Interestingly, BAT
also contains a type II deiodinase whose activity increases
in response to cold, thereby enabling BAT to have the
important ability to regulate intracellular T3 concentration in a tissue-specific manner (469, 470). This increase in
T3 concentration likely saturates nuclear TRs and enhances norepinepinephrine stimulation of UCP. The adrenergic stimulation in BAT is predominantly, but not
exclusively, mediated by brown fat specific adrenergic
␤3-receptors. The dual regulation of UCP by the type II
deiodinase and the adrenergic system suggests convergence of nuclear- and membrane-signaling systems in the
transcriptional regulation of these important target genes
in BAT, but the precise relative contributions and interplay between these regulatory systems need to be further
defined. Lowell et al. (313) used the UCP promoter to
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
the heart such as the voltage-gated potassium channel
Kv1.5, Na⫹-K⫹-ATPase, and the hyperpolarizaton activated cyclic nucleotide-gated channel (365, 379, 572). Additonally, TH can regulate ␤-adrenergic receptor number
in the heart and may thereby enhance sensitivity to catecholamines (558).
Recently, a dominant negative mutant TR␤ was targeted to the heart in transgenic mice. ␣-MHC and SERCA2
mRNA were decreased, but ␤-MHC mRNA was increased,
in the hearts of the transgenic mice (166). Cardiac muscle
contraction was prolonged, and the QRS interval was
prolonged on electrocardiogram (EKG). TR␣ ⫺/⫺ knockout mice showed decreased heart rate and QRS interval
prolongation on EKG, whereas TR␤ ⫺/⫺ knockout mice
had elevated heart rate that was unresponsive to TH
administration (228, 552). These findings suggest that
TR␣-1 may have a major role in maintaining baseline heart
rate, whereas TR␤ may mediate TH stimulation of heart
rate.
Finally, a novel and potentially exciting therapeutic
use of T3 as an inotropic agent has been in cardiac surgery. Novitsky (356) showed improved cardiac function
and hemodynamics when brain-dead organ donors were
pretreated with T3 and cardiac transplant recipients were
treated with T3 postoperatively. A small group of patients
that underwent cardiac bypass surgery and were treated
postoperatively with T3 also showed some benefit (357).
However, a large randomized study showed that although
T3 increased cardiac output and decreased systemic vascular resistance in patients who underwent coronaryartery bypass surgery, there was no improvement in outcome or changes in postoperative therapy (249).
Volume 81
July 2001
THYROID HORMONE ACTION
D. Liver
TH has multiple effects on liver function including
stimulation of enzymes regulating lipogenesis and lipolysis as well as oxidative processes (375, 376). Some of the
lipogenic enzymes that are regulated are malic enzyme,
glucose-6-phosphate dehydrogenase, and fatty acid synthase. In the case of malic enzyme, which has been studied extensively, there is a biphasic induction of the malic
enzyme mRNA at 4 and 24 h, suggesting that there may be
an initial direct stimulation by T3 and a secondary effect
due to stimulation by other gene products that are regulated by T3 (486). Indeed, it recently has been shown that
Spot 14 (S14), a protein that originally was identified by
two-dimensional gel electrophoresis of the translational
products of total hepatic tissue mRNA from T3-treated
rats, may regulate a number of lipogenic enzymes, including malic enzyme, in the liver (245, 452). Likewise, at least
in the rat, a number of lipogenic enzymes also may be
regulated by growth hormone, which is induced by T3
(375). Interestingly, malic enzyme is very sensitive to T3 in
the liver, but it is unresponsive in the brain, suggesting
that tissue-specific factors are important in determining
T3-mediated stimulation of transcription. Nikodem and
co-workers (395) identified a putative TRE in the promoter region of the malic enzyme gene that contains two
half-sites arranged as direct repeats separated by four
nucleotides.
T3 regulation of malic enzyme gene transcription also
can be regulated by carbohydrate intake, insulin, and
cAMP. For instance, T3 effects on malic enzyme gene
transcription are minimal in fasted animals but are most
pronounced in animals fed a sucrose-containing fat-free
(lipogenic) diet (375, 376). Similar interactions between
T3 and dietary carbohydrate also occur in the gene regulation of other lipogenic enzymes. Another T3-regulated
gene expressed in liver that has been studied extensively
has been the one encoding S14 protein (376). Its mRNA is
rapidly induced by T3 after 20 min in hypothyroid rats and
precedes the expression of lipogenic enzymes. Additionally, it is coregulated by carbohydrate similar to lipogenic
enzymes. Its tissue distribution is similar to those of
lipogenic enzymes as it is expressed in liver, white and
brown fat, and lactating mammary tissue. Recently, it has
been shown that S14 may be localized in the nuclear
matrix and thus may participate in regulating the transcription of lipogenic enzymes (245, 246).
It has been appreciated for many years that hypothyroidism is associated with hypercholesterolemia with elevated serum intermediate and low-density lipoprotein
(LDL) cholesterol concentrations (52). The major mechanism for these effects may be lower cholesterol clearance resulting from decreased LDL receptors. Furthermore, the genotype of the LDL receptor gene may
influence the elevation of serum LDL cholesterol concentrations in hypothyroid patients and their response to
thyroxine treatment (559). An additional mechanism may
be decreased hepatic lipase activity in hypothyroidism
which decreases conversion of intermediate-density lipoproteins to LDL and high-density lipoprotein metabolism (380, 508). It is not known whether these effects are
mediated directly or indirectly by TH. Several putative
TREs in the distal promoter region of the hepatic lipase
and apoliporotein A1 genes have been identified (457,
513). TH also has been shown to regulate the expression
of several important proteins and enzymes involved in
cholesterol metabolism and synthesis such as the LDL
receptor, cholesterol ester hydrolase, and cholesterol
acyltransferase (423, 447, 461). TH also may regulate posttranscriptional editing of apolipoprotein mRNA (111).
TR␤-1 is the predominant isoform expressed in liver,
whereas TR␣-1 is the major isoform expressed in heart
(128, 204, 487). These differences in TR isoform expression have spawned attempts to develop isoform-specific
TH analogs that may have cholesterol-lowering effects
but minimal cardiac toxicity (86, 512, 533).
Recently, Hayashi and Refetoff (195) have created a
mouse model of TH resistance in the liver by transfecting
hepatocytes with adenovirus vectors encoding a mutant
TR (195). This mutant receptor had dominant negative
activity (see below) on wild-type receptor function. The
mice that expressed the mutant TR had elevated serum
cholesterol levels compared with control animals in both
hypothyroid and hyperthyroid states. Additionally, they
had blunted induction of S14 protein and 5⬘-deiodinase
mRNA by T3. These findings suggest a direct role by TRs
in regulating these genes. This model thus may be a useful
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
target diptheria toxin to BAT in transgenic mice. These
animals had decreased amounts of BAT, resulting in decreased cold tolerance and obesity, and suggesting a critical role for BAT in these functions. Recently, UCP3
knockout mice were generated and had normal weight,
thermogenesis, and response to T3, suggesting that UCP3
is not the main mediator for TH-mediated thermogenesis
as originally proposed, or alternatively, compensatory
mechanisms can overcome the lack of UCP3 (169, 538).
Several human studies have shown that chronic hypo- and hyperthyroidism as well as acute T3 treatment did
not affect serum leptin levels (100, 264, 319, 480). However, one study showed that hypothyroid patients had
increased leptin levels, but the increase correlated with
adiposity (399). Another study showed that hyperthyroid
patients treated with thiamazole increased their leptin
levels (610). Studies in the rat have shown that T3 can
decrease leptin levels, but it is not known whether this is
due to a direct effect or due to its effects on fat mass (125,
302, 497).
1119
1120
PAUL M. YEN
E. Pituitary
TH regulates the synthesis and secretion of several
pituitary hormones. Absence of GH has been observed in
the pituitaries of hypothyroid rats (440). Additionally, T3
can stimulate the transcription of GH mRNA and GH
synthesis in rat pituitary tumor cells (322, 440, 458). Brent
et al. (54) identified a rGH TRE than contains a direct
repeat separated by four nucleotides and a palindromic
sequence (101, 281). This HRE can also confer sensitivity
to retinoids and vitamin D (156, 493). However, in contrast to rodents, T3 has limited ability to regulate GH
synthesis in humans. For example, hypothyroid children
have impaired growth but serum growth hormone levels
are normal (424, 537). Cotransfection studies using the
human growth hormone promoter have not shown stimulation by TH (55, 71). Studies in cultured human somatotrope adenomas showed that T3 stimulated GH release
but had variable effects on transcription (90).
TH also can negatively regulate thyrotropin (TSH)
transcription by direct and indirect mechanisms (464). TH
can negatively regulate TRH at the transcriptional level,
which in turn decreases transcription of TSH mRNA (465,
573). T3 also can downregulate prolactin mRNA by a
similar mechanism, and also by direct effects on transcription (565). The TRH promoter has been analyzed and
contains several nTREs (206, 446). TH hormone also can
negatively regulate TSH by decreasing transcription of the
glycoprotein hormone ␣-subunit (common to TSH, luteinizing hormone, follicle-stimulating hormone, and human
chorionogonadotropic hormone) and the TSH␤ subunit
genes (44, 51, 77, 108, 318, 464, 466). Several nTREs in the
promoters of these genes have been described. In some
cases, they contain single half-sites, suggesting that TR
monomers may be involved in negative regulation. Addi-
tionally, these genes display ligand-independent activation in cotransfection studies (207, 501). It also is possible
that corepressors, rather than coactivators, may participate in this activation and negative regulation (207, 445,
501). Additionally, it has been shown that TH decreases
the stability of TSH␤ mRNA by inducing shortening of its
poly(A) tail (263). T3 can stimulate a cytosolic RNA-binding protein to bind to the 3⬘-untranslated region of TSH␤
mRNA and may thereby regulate mRNA stability at a
posttranscriptional level (299).
Recent cotransfection and knockout studies suggest
that TR␤-2 isoform may be playing the predominant role
in regulating TSH (2, 275). In situ hybridization and immunostaining studies have shown that TR␤-2 is highly
expressed in thyrotropes in the pituitary (87, 590). Additionally, RXR␥ isoform appears to be selectively expressed in thyrotropes, suggesting that it also may play a
functional role in the regulation of TSH via isoform-specific TR/RXR complexes or RXR␥ homodimers (193, 495).
Recent findings of inappropriate TSH secretion in a RXR␥
knockout mice, and the suppression of TSH by RXRspecific agonist in humans are consistent with this model
(192, 462).
F. Brain
TH has major effects on the developing brain in utero
and during the neonatal period (38, 373). Neonatal hypothyroidism due to genetic causes and iodine deficiency in
humans can cause mental retardation and neurological
defects. Studies in hypothyroid neonatal rats have shown
that absence of TH causes diminished axonal growth and
dendritic arborization in the cerebral cortex, visual and
auditory cortex, hippocampus, and cerebellum (409, 410).
In the cerebellum, absence of TH also delays proliferation
and migration of granule cells from the external to the
internal granular layer. The critical role of TH is further
demonstrated by a recent report in which a dominant
negative TR was targeted to the cerebellum in transgenic
mice. The Purkinje cells showed decreased dendritic arborization, while the granule cells had retarded migration
to the internal granular layer (257). The developmental
delays in the rat brain can be reversed if TH is administered within 2 wk after birth (539). These findings support
the clinical observations that early T4 treatment of congenital hypothyroidism prevents intellectual impairment
in humans and is the major impetus for neonatal screening for congenital hypothyroidism. In utero, monodeiodination of T4 to T3 by type II deiodinase and maternal-fetal
transfer of T4 may help maintain normal T3 concentrations even when the fetus has congenital hypothyroidism
(110, 180). Additionally, maternal transfer of thyroxine
may be important, particularly during early fetal development (68, 542). Recent studies have suggested that mater-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
tool for determining those hepatic genes that are directly
regulated by TH.
To identify novel hepatic target genes and examine
gene profiles regulated by T3, Feng et al. (136) used a
quantitative fluorescent cDNA microarray to identify hepatic genes regulated by TH. Fifty-five genes, 45 of which
were not previously known to be TH responsive, were
found to be regulated by TH (136). Among them, 14 were
positively regulated by TH, and surprisingly, 41 were negatively regulated. TH had broad effects as it regulated
gene expression of a diverse range of cellular pathways
and functions such as gluconeogenesis, lipogenesis, insulin signaling, adenylate cyclase signaling, cell proliferation, and apoptosis. This application of the microarray
technique to study hormonal regulation of gene expression in vivo demonstrates the value of large-scale gene
expression analyses for future studies of hormone and
drug action.
Volume 81
July 2001
THYROID HORMONE ACTION
silence T3-responsive target genes during embryogenesis.
One proposed candidate suppressor may be the orphan
receptor, COUP-TF, which binds to the suppressor region
in the Pcp2 promoter (16). It remains controversial as to
whether these cerebellar genes are specifically regulated
by TR␤-1, which is expressed in parallel. Studies in cultured oligodendrocytes have suggested that this may be
the case (69, 425); however, no significant developmental
delays in Pcp2 and MBP expression were observed in TR␤
knockout mice (443). Finally, it is possible that there may
be cross-talk between TR and other transcription factors
in the regulation of target genes in the brain. The knockout mouse for the orphan receptor, ROR (staggerer), has
cerebeller defects that are almost identical to those observed in hypothyroid mice (258). In this connection, ROR
has been shown to modulate transcriptional activity by
TH in cotransfection studies (260).
X. RESISTANCE TO THYROID HORMONE
RTH is a syndrome in which patients have hyposensitivity to TH, elevated circulating serum T3 and T4, and
elevated or nonsuppressed TSH levels. Refetoff et al.
(414) first described this syndrome in two siblings who
presented with deaf-mutism, delayed bone age with stippled epiphyses, goiter, and high protein-bound iodine levels. Since this initial report, over 350 subjects have been
described who have RTH, with ⬃80% of the subjects
inheriting this disorder (7, 60, 415). The clinical manifestations are variable among families with RTH and also
among affected family members. Additionally, patients
can have clinical symptoms that have features of hypoand hyperthyroidism, suggesting variable resistance in
different tissues. Some of the clinical features that have
been described include goiter, mental retardation, attention-deficit disorder, tachycardia, delayed bone growth
and maturation, and hearing abnormalities. There also are
examples of pituitary resistance to TH (PRTH), in which
patients have resistance predominantly in the pituitary
and have signs and symptoms of hyperthyroidism in peripheral tissues (7, 60, 415).
With the exception of the index family, which had
autosomal recessive inheritance, RTH displays autosomal
dominant inheritance (415). In 1988, Usala et al. (535)
demonstrated a tight linkage between the TR␤ gene locus
and RTH by restriction fragment length polymorphism.
Soon afterwards, two groups independently demonstrated mutations in the LBD of TR␤ in patients from two
families with RTH: glycine-345 replaced by arginine (Mf1), or proline-453 replaced by histidine (438, 536). Subsequent characterization of other families with RTH have
shown TR␤ point mutations in the two major “hot spots”
that cluster near these original mutations (Fig. 13) (36,
415). Mutations also have been found in a third “hot spot”
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
nal thyroid status may have significant effects on the
neuropsychological outcome of children (38, 182, 403).
The ontogeny of TR isoforms in the brain suggests
that specific TR isoforms may be involved in transcription
of target genes and in brain development (373, 487).
TR␣-1 is expressed throughout the brain from early fetal
development and accounts for total T3 binding in the fetal
brain. TR␤-1 is absent or minimally expressed, except in
a few selected areas such as the cochlea and cerebellum
(47, 48, 488, 489). However, there is a dramatic 40-fold
increase in TR␤-1 mRNA expression throughout the brain
shortly after birth that reaches maximum levels 10 days
afterward, and then persists until adulthood (487). In
contrast, TR␣-1 and c-erbA␣-2 mRNA undergo a transient
twofold increase that decreases to adult levels 2 wk after
birth. This early rise in TR␤-1 expression coincides with
the neonatal surge in serum T3 and suggests there may be
a coordinated temporal developmental program in which
critical target genes are regulated by specific TR isoforms.
Similar temporal patterns of expression also have been
observed in the chick and amphibian tadpole (127, 137,
473).
Despite the importance of TH in brain development,
there are relatively few genes known to be directly regulated by TH, and many have only been partially characterized. Farsetti and co-workers (129, 130) have shown
that the gene for myelin basic protein (MBP) is directly
regulated by TH and have identified a TRE at position
⫺186 to ⫺169 of the MBP promoter. Recent studies of
brain-derived neutropic factor showed that TH can regulate its expression in a promoter-, developmental-, and
region-specific manner (259). TH also regulates several
genes that are involved in a wide range of cellular functions: glutamine synthase, protein kinase C, substrate
RC3/neurogranin, prostaglandin D2 synthase, hairless (a
potential transcription factor), and adhesion molecules
such as neural cell adhesion molecule and matrix proteins
such as tenascin, and proteins important for neuronal
migration (14, 15, 155, 172, 323, 515). Nordquist et al. (355)
have identified several genes that are expressed in the
cerebellum: calbindin, myo-inositol trisphosphate (OP-3)
receptor, and Purkinje cell protein-2 (Pcp2). Study of the
mRNA expression of these genes and MBP in the cerebellums of hypothyroid and euthyroid neonatal mice showed
that the expression of these genes was delayed in the
absence of hormone but eventually reached similar expression levels (489). These data also suggested that there
may be three phases in the regulation of these particular
genes: a refractory prenatal period, a T3-responsive period
typically from postnatal days 3–20, and a T3-independent
period. Identification of a putative silencing element in
the promoter of Pcp2 promoter that may be functional
during fetal development provides support for this model
(16). It is intriguing to speculate there may be developmentally and regionally expressed suppressors that may
1121
1122
PAUL M. YEN
Volume 81
FIG. 13. Diagram of “hot spots” in the
ligand-binding domain of TR␤ where natural mutations have clustered. Shown
are some representative mutations. For a
more extensive listing of mutations, see
Refs. 7, 60, 415 and resistance to thyroid
hormone (RTH) registry at the University of Chicago (via internet: gopher.
uchicago.edu/subfolder medicine/RTH
registry).
observation suggested that a single copy of TR␤ is sufficient for normal function. Furthermore, it suggests that
reduction of TR␤ (i.e., gene dosage) did not account for
the autosomal dominant inheritance seen in other RTH
patients. Instead, it strongly suggested that TR␤ point
mutations interfere with the normal function(s) of TRs.
This interference of wild-type protein function by a mutant protein has been called “dominant negative activity”
(223, 582). The amount of dominant negative activity by a
mutant TR depends in part on the level of mutant receptor
expression. For example, a patient who was homozygous
for mutations in both TR␤ alleles had severe RTH and
mental retardation (371). In contrast, his parents who had
mutations in only one TR␤ allele had mild RTH.
Within any given cell in a RTH patient, mutant TR␤ as
well as wild-type TR␤ and TR␣ are expressed. The molecular mechanism(s) for the dominant negative activity
by the mutant TR␤ on wild-type TR function has been the
subject of numerous studies. Transient cotransfection
studies show that natural TR␤-1 mutations not only fail to
mediate normal T3-regulated transcription, but also block
the T3-regulated transcription by normal TRs (78, 327,
415, 437). The mechanism for this dominant negative
activity likely involves binding to TREs by inactive mutant
homodimers or TR/RXR heterodimers that cannot bind T3
and hence cannot activate transcription of target genes.
Indeed, DNA binding of mutant TRs and v-erbA is required
for their dominant negative activity. Additionally, some
natural mutant TR␤-1s, as well as v-erbA, constitutively
repress basal transcription even in the presence of T3 (28,
104, 345, 398, 582, 592). Recent experiments also suggest
that dimerization may play an important role in mediating
dominant negative activity (94, 196, 344). However, it is
not known whether a particular mutant TR complex (i.e.,
homodimer or heterodimer) mediates this activity in all
cases. Heterodimer-specific mutants are able to mediate
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
in the most amino-terminal portion of the LBD (37, 97,
370, 400, 571). Most patients have mutations due to single
amino acid substitutions at a single codon, although single amino acid deletions, frameshift mutations, and truncations due to premature termination of translation from
a mutation-generated stop codon also have been identified (7, 60, 415). Almost all mutations cluster around the
ligand-binding pocket observed in the TR LBD crystal
structure. In vitro transcription and translation of the
mutant receptors typically show minimal or reduced T3binding affinity (415).
Approximately 60 different mutations in TR␤ have
been identified in RTH patients from over 100 families (7,
60, 415). In some cases, the same mutations have been
described in different families. The clinical phenotype can
vary among these families that harbor the same mutation
and also vary within a family. This suggests that there may
be other genetic modifiers that determine the phenotype.
In this connection, the same mutation can cause either
GRTH or PRTH in different individuals even within the
same family. In general, there does not seem to be a
strong correlation between particular mutations and the
development of GRTH and PRTH. The R338W mutation,
and a ninth heptad mutant, R429Q, may be more prone to
a PRTH phenotype; however, patients with these mutations also can exhibit GRTH (7, 140, 415). Interestingly, no
germline TR␣-1 mutants have been described thus far in
humans. It is possible that TR␣-1 mutations are lethal in
utero, silent, and/or exceedingly rare.
Analyses of the TR␤ gene in the index family with
RTH showed that the affected members were homozygous for the deletion of the entire coding region of TR␤
(502). Thus complete lack of TR␤ expression was compatible with life. Interestingly, heterozygous members of
the family that contained only one deleted TR␤ allele had
normal clinical and laboratory findings (Fig. 14). This
July 2001
THYROID HORMONE ACTION
1123
dominant negative activity, albeit more weakly than other
mutants that can form heterodimers (189, 196). Amino
acid substitutions in the ninth heptad of TR␤-1 mutants
decreased heterodimerization and dominant negative activity of TR␤-1 mutants (21, 94, 344). These observations
have been used to support functional roles for either
mutant homo- or heterodimers. However, it may turn out
that transcriptionally inactive homo- and heterodimers
both can mediate dominant negative activity as long as
they compete effectively with wild-type TRs for binding to
TREs.
Dominant negative activity in cotransfection studies
and severity of clinical phenotype correlate well with
impairment of in vitro T3 binding by mutant TR␤s (327,
415), although some exceptions have been reported (196,
343). Recent studies on TR␤ mutations in the AF-2 region
and hinge region have shed some light on this issue. TR␤
mutations in the AF-2 region have normal T3 binding,
DNA binding, and heterodimerization but are transcriptionally inactive in the presence of ligand due to their
inability to interact with coactivators (521). Recently, several groups have described RTH patients who have TR␤
mutations in the AF-2 region (96, 498, 549). Furthermore,
AF-2 mutants had potent dominant negative activity on
wild-type TRs in cotransfection studies (96, 311, 506).
Recently, several mutations in the third hot spot also have
been characterized. Two mutants (R243Q and R243W)
had normal T3-binding affinity but transactivated poorly in
the presence of T3 (97, 370, 435, 571). These mutants also
exhibited dominant negative activity on wild-type TR. One
study showed that mutant homodimers could not be
readily dissociated by T3, suggesting that these receptors
may have reduced T3-binding affinity after binding to DNA
(571). Additionally, some of these mutants may have impaired corepressor release or interaction with coactivators (97, 435).
Yoh et al. (593) have studied SMRT corepressor interaction with a battery of mutant TRs. They observed
that mutant TRs had defective dissociation from this corepressor. In general, the release of SMRT correlated with
the T3-binding affinity of the mutant receptors. However,
two mutants that had only mildly impaired T3 binding
affinity were unable to dissociate SMRT even at 1 ␮M T3.
Additionally, two mutants, D432M and D432G, have enhanced association with SMRT. In general, the amount of
dominant negative activity correlated with the impairment of SMRT dissociation in the presence of T3. The
authors also showed that hinge region mutants that abrogate SMRT interaction also decrease the dominant negative activity. Tagami and Jameson (499) also found similar
results when they studied NCoR interaction with a battery
of TR mutants. They also observed that a hinge region
mutant that abrogated NCoR interaction decreased basal
repression of transcription of positively regulated genes
and ligand-independent activation of negatively regulated
genes. These findings suggest that NCoR could play a role
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
FIG. 14. Gene dosage does not explain RTH phenotype. Top: point mutation in TR␤ gives RTH phenotype.
Bottom: deletion of one TR␤ allele gives no phenotype.
Deletion of both TR␤ alleles in patients gives severe RTH
phenotype.
1124
PAUL M. YEN
dominant negative activity on wild-type TR. In this connection, a transgenic mouse that overexpressed v-erbA
also developed hepatomas (32). A somatic mutation of
TR␤ has been identified in a thyrotropin-secreting tumor
and may cause the defective negative regulation observed
in these pituitary tumors (18).
There have been two reported cases of hypersensitivity to TH (222, 320). One patient was euthyroid on the
basis of thyroid function tests but had a marked tachycardia. Analyses of T3 binding in lymphocytes showed
normal binding affinity but increased binding capacity.
Family history showed several family members with paroxysmal tachycardia and elevated T3 binding in lymphocytes. Sequencing of exons 9 and 10 of TR␤ showed no
mutations. Another patient had serum thyroid function
tests suggestive of hypothyroidism but exhibited no clinical symptoms suggestive of hypothyroidism. This patient
had a V444A substitution in TR␤ resulting in increased
affinity for T3. A constitutively active estrogen receptor
with a mutation in the AF-2 domain has been described
(546), so it is theoretically possible that mutations that
enhance interaction with coactivators could generate a
TR with constitutive activity or increased ligand-mediated
transcription.
XI. GENETICALLY ENGINEERED MOUSE
MODELS OF THYROID HORMONE ACTION
Transgenic expression of dominant-negative mutant
TRs, and the targeted gene inactivation or knockout of TR
isoforms, have been used to study TH action in mice.
These mouse models have provided new information on
the developmental and physiological effects of TH.
Two groups have examined the effects of ubiquitous
expression of v-erbA and a natural mutant TR␤-1 in transgenic mice (32, 564). These transgene products have dominant negative activity on the actions of wild-type TR. The
mice that expressed v-erbA had multiple abnormalities
including hypothyroidism (due to follicular disorganization in the thyroid), inappropriate TSH response, enlarged
seminal vesicles, hepatomas, decreased fertility, and reduced adipose tissue. Because v-erbA has dominant negative activity on retinoic acid-mediated transcription, it is
possible that some of the observed effects may not be due
solely to blockade of T3-mediated transcription. The
transgenic mice that expressed mutant TR␤-1 had elevated T3, inappropriately normal TSH, behavioral abnormalities, decreased fertility, and decreased weight. These
findings resembled the clinical phenotype observed in
RTH patients harboring this mutation.
Pituitary-specific targeting has been undertaken using natural dominant negative mutants (TR␤ G345R,
⌬337T) under the regulation of the TSH␤ or glycoprotein
hormone ␣-subunit promoters (4, 197). These transgenic
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
in mediating dominant negative activity of mutant TRs in
positively and negatively regulated target genes. Additionally, mutant TR␤s located between the two major hot
spots or near the AF-2 region also had impaired corepressor release (92, 436, 498).
Liu et al. (311) studied the interaction of mutant TRs
with the corepressor NCoR and coactivator SRC-1. The
G345H mutant, which has minimal T3 binding affinity,
remained bound to NCoR in the presence of T3 and was
unable to bind SRC-1. An AF-2 mutant could release
NCoR in the presence of T3 but was unable to bind SRC-1.
Both mutant receptors had potent dominant negative activity. A mutant receptor (R320H) with threefold lower T3
binding affinity than wild-type TR was able to release
NCoR at higher T3 concentrations and recruit SRC-1 at
higher T3 concentrations. Interestingly, this mutant had
potent dominant negative activity at low T3 concentrations but weaker dominant negative activity at higher
concentrations. Similarly, Chatterjee and co-workers (96,
97) have identified helix 3 and helix 12 mutants from
patients with RTH that have impaired recruitment of coactivators. These findings and those showing impaired
corepressor release by mutant TR␤s (435, 498, 593) reinforce the notion that inability to release corepressors
and/or the inability to recruit coactivators (regardless of
the mechanism) can result in TR complexes that cannot
be activated by ligand and can mediate dominant negative
activity.
Refetoff and co-workers (401, 548) recently have reported families with RTH that did not contain TR␤ mutations. Additionally, linkage analyses suggested that RTH
was not associated with TR␣. Nuclear extracts from affected patients showed an additional TR-associated band
on electrophoretic mobility shift assay (548). These findings suggest the possibility that mutations in cofactors or
dysregulation of their expression may be involved in the
RTH phenotype of these families. Currently, there is no
direct evidence for such “postreceptor” defects. In one
example of a coactivator mutation associated with human
disease, mutations in CBP were found in patients with
Rubinstein-Taybi syndrome (393), an autosomal dominant
disorder in which patients have mental retardation, short
stature, and craniofacial abnormalities. However, thyroid
function tests in these patients were surprisingly normal,
suggesting one normal allele is sufficient for TH signaling
(367). Ando et al. (18) recently observed an intraexonic
splice variant of TR␤ in a TSH-secreting adenoma that
may account for pituitary resistance to TH in that tumor.
Thus it is possible that nongenomic mechanisms may
account for RTH in some of these families.
There also have been several somatic TR mutations
described in tumors. Lin et al. (309) have described somatic mutations in TR␣ and TR␤ from a human hepatoma
cell line. It is not known whether these mutant TRs contributed to oncogenesis, although they both exhibited
Volume 81
July 2001
THYROID HORMONE ACTION
genic mice that lack only TR␣-1 (TR␣-1 ⫺/⫺) have a
milder phenotype with decreased body temperature and
heart and prolonged Q-T interval on EKG (552). These
findings suggest a major role for TR␣-1 in regulating cardiac function. The differences between the two phenotypes could be due to specific functions of c-erbA␣-2,
although specific knockout of c-erbA␣-2 did not affect
survival of the pups (151). Samarut and co-workers (75)
have reported generation of short TR isoforms from internal translation start sites that can block the actions of
TR. It is likely that these TR isoforms may be responsible
for the more severe phenotype of the TR␣ ⫺/⫺ knockout
mice. Indeed, a TR␣ knockout that lacks both TR␣-1 and
c-erbA␣-2 and does not express these isoforms (TR␣ o/o)
has a milder phenotype than TR␣ ⫺/⫺ and increased T3
sensitivity in tissues expressing TR␤ (316a).
Ablation of TR␤ by homologous recombination in
mice (TR␤ ⫺/⫺) produced modest changes in phenotype
with elevated TSH and T4, thyroid hyperplasia, as well as
hearing defects as the major findings (149, 150). These
findings involving the HPT axis resemble those seen in
patients with RTH. Deafness was observed in the index
cases of RTH which had deletion of TR␤ (414). Taken
together, these findings suggest a critical role for TR␤ in
the development of the auditory system. Interestingly,
ligand-independent elevation of TSH is normal in hypothyroid TR␤ ⫺/⫺ mice, but the suppression of TSH by TH
is impaired (547). Recently, TR␤-2 has been selectively
knocked out (2). These mice had elevated levels of TH
and TSH, implicating TR␤-2 as the major regulator of TSH.
Interestingly, these mice did not have any hearing defects.
These findings suggest that TR␤-2 may not be critical for
auditory development, or its function may be compensated by TR␤-1. Finally, recent studies in TR␤ ⫺/⫺ mice
suggest TR␤2 may be involved in retinal development
(353a).
Given the relatively mild phenotypes of the TR␣-1
and TR␤ knockout mice, it is likely that the two isoforms
may have redundant transcriptional activity and can compensate for each other in most target genes. To examine
the effects of abolishing all TR isoforms, TR␣-1 ⫺/⫺ TR␤
⫺/⫺ knockouts have been generated (171). These mice
lack TR␣-1 and TR␤, but still express c-erbA␣-2. These
mice have markedly elevated T4, T3, and TSH with large
goiters. These mice also have growth retardation and
decreased fertility, as well as impaired bone development
and reduced bone mineral content. These mice also have
reduced heart rate and impaired control of body temperature, similar to the TR␣-1 ⫺/⫺ mice. Although these mice
have many symptoms of hypothyroidism, these mice did
not have any reduction in activity level. There was no
measurable T3 binding in liver and brain nuclear extracts,
confirming the absence of any TR in these mice.
TR␣ ⫺/⫺//TR␤ ⫺/⫺ knockout mice which lack
TR␣-1, c-erbA␣-2, and TR␤, but express short TR␣ iso-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
mice had slightly elevated T4, elevated TSH, inability to
suppress TSH after T3 administration, and decreased cholesterol. These findings are consistent with TH resistance
in the pituitary and TH sensitivity in the liver. Interestingly, one line (⌬337T) had a blunted rise in TSH compared with littermate controls, suggesting the mutant TR
may block the ligand-independent activation of TSH (4).
In contrast to these two studies, another transgenic line in
which a frameshift mutant TR (448 frameshift) was targeted to the pituitary with the glycoprotein hormone
␣-subunit did not show any abnormalities in the HPT axis
(606). It is possible that differences in the expression
levels of the mutant TRs may account for this difference
in phenotype.
Cardiac-specific targeting of TR␤ ⌬337T has resulted
in transgenic mice with abnormal papillary muscle contraction and a prolonged QRS on EKG (166). ␣-Myosin
heavy chain and sarcoplasmic reticulum Ca2⫹-ATPase
mRNA were decreased, whereas ␤-myosin heavy chain
mRNA was increased in transgenic mice. These findings
are similar to those observed in the hypothyroid heart;
however, they contrast with the situation in patients with
RTH who often have resting sinus tachycardia. The heart
normally expresses mostly TR␣ and little TR␤, so the
finding in RTH patients may be due to the relatively low
amount of dominant negative TR␤ in the context of elevated circulating TH levels (415). Another study in which
the same mutant TR␤ was targeted to the heart showed
decreased contractility in isolated heart preparations
(386).
Hayashi et al. (195) have used an adenovirus-based
expression system encoding a dominant negative TR␤-1
mutant, G345R, to create a liver-specific model of RTH
(195). They utilized the selective clearing and uptake of
injected adenovirus vector by the liver and enabled them
to efficiently transfect hepatocytes with either TR␤ or
G345R. They demonstrated resistance to T3 in G345Rtransfected mice by measuring T3 regulation of several
liver enzymes. Interestingly, serum cholesterol increased
more in the TR␤ and G345R transfected mice compared
with controls. These findings suggest that unliganded
wild-type TR␤ and G345R both may have effects on target
genes in the cholesterol synthesis pathway.
Two different groups generated TR␣ knockout mice
that have different phenotypes (152, 552). The structure of
the TR␣ gene is complex because it encodes TR␣-1,
c-erbA␣-2 (which cannot bind T3), and rev-erbA (generated from the opposite strand encoding TR␣) so the locus of
homologous recombination will determine which isoforms will be knocked out (293). Transgenic mice in
which both TR␣-1 and c-erbA␣-2 have been deleted (TR␣
⫺/⫺) have a more severe phenotype with hypothyroidism, intestinal malformation, growth retardation, and
early death shortly after weaning (152). The early death
can be partially rescued by T3 injection of pups. Trans-
1125
1126
PAUL M. YEN
elevated T4, T3, and moderately elevated TSH levels. Interestingly, suppression of TSH by T3 was impaired in
knockout mice, suggesting that SRC-1 may be needed for
the negative regulation of TSH production. These findings
have clinical implications because several familes with
RTH have been described that do not have mutations in
TR␣ or TR␤ genes. It is possible that mutations in cofactors may account for their RTH phenotype. Additionally,
as knockout mice for various coactivators are generated,
they will be useful tools in studying TH action on both
positively and negatively regulated genes and the effects
of coactivators on the function of the HPT axis.
XII. CONCLUSION
Just as our early knowledge of TH action was interwoven with many of the key developments in biomedical
science, so it has been the case for the recent study of TH
action. Even more than before, our knowledge has benefited from the contributions of outstanding investigators
from many different fields and countries. With the recent
sequencing of the human genome and the development of
new technologies such as microarrays, proteomics, and
genetically engineered mouse models, we will have powerful new tools to study the complexities of TH action in
the future. It is with eagerness that we look forward to an
even deeper understanding of TH action.
I thank Drs. Sheue-Yann Cheng (National Cancer Institute),
Edward Rall [National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK), National Institutes of Health], Leonard Kohn (NIDDK), Samuel Refetoff (Univ. of Chicago), Nicholas Sarlis (NIDDK), and Roy Weiss (Univ. of Chicago) for their
helpful discussions and criticisms. I also thank members of my
laboratory: Drs. Stephen Angeloni, Shinichiro Ando, Xu Feng,
Padma Maruvada, and Pnina Rotman for their constructive comments.
Address for reprint requests and other correspondence:
P. M. Yen, Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, NIDDK, NIH, Bethesda,
MD 20892 (E-mail: [email protected]).
REFERENCES
1. ABE T, KAKYO M, TOKUI T, NAKAGOMI R, NISHIO T, NAKAI D, NOMURA H,
UNNO M, SUZUKI M, NAITOH T, MATSUNO S, AND YAWO H. Identification
of a novel gene family encoding human liver-specific organic anion
transporter LST-1. J Biol Chem 274: 17159 –17163, 1999.
2. ABEL ED, BOERS ME, PAZOS-MOURA C, MOURA E, KAULBACH H, ZAKARIA
M, LOWELL B, RADOVICK S, LIBERMAN MC, AND WONDISFORD F. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest 104: 291–300, 1999.
3. ABEL ED, KAULBACH E, BOERS HC, AND WONDISFORD FE. Elevated
thyroid hormone levels in transgenic mice with pituitary overexpression of a mutant B1 thyroid hormone receptor. Thyroid 6: S-82,
1996.
4. ABEL ED, KAULBACH HC, CAMPOS-BARROS A, AHIMA RS, BOERS ME,
HASHIMOTO K, FORREST D, AND WONDISFORD FE. Novel insight from
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
forms have been generated (157). They have a similar
phenotype as the TR␣ ⫺/⫺ mice except for markedly
elevated T4, T3, and TSH, and more pronounced malformation in the ileum. TR␣ o/o//TR␤ ⫺/⫺, which lack the
TR␣-1, c-erbA␣-2, and TR␤-1 as well as the shorter TR␣
isoforms, survive until 6 mo of age and have a similar
phenotype similar to the TR␣-1 ⫺/⫺//TR␤ ⫺/⫺ mice
(171). However, the females are completely sterile, and
the males have decreased fertility. They also have markedly elevated T4, T3, and TSH. Comparison of the the
latter two double-knockout strains in addition to the
c-erbA␣-2 knockout mice (151) should provide information on the specific role of c-erbA␣-2 on development and
thyroid function.
The preceding double-knockout mouse studies demonstrate that absence of TRs is not incompatible with life
and that mice without TRs can survive suprisingly well.
Many of the effects on peripheral tissues were milder in
the double-knockout mice than those seen in congenital
hypothyroidism. The reason(s) for these observations is
not known. Given the lack of T3 binding in nuclear extracts of the TR␣ ⫺/⫺//TR␤ ⫺/⫺ mice, it is unlikely there
is an additional TR isoform unless it is expressed during
embryogenesis or in very limited subset of cells. It is
possible that nongenomic effects of TH may be active in
the double-knockout mice but not in congenital hypothyroidism. It also is possible that lack of TRs is less deleterious than having TRs present during hypothyroidism.
Given the role of unliganded TRs and corepressors in
repressing basal transcription, it is possible that critical
target genes may be shut down in the hypothyroid mice,
whereas a certain degree of “leaky” basal transcription
occurs in the double-knockout mice.
Recently, Cheng and co-workers (236) have generated a “knock-in” mouse model in which a mutant TR was
introduced into the endogenous TR␤ gene locus. Similar
to patients with RTH, the heterozygous mice had elevated
serum T4 and TSH, mild goiter, hypercholesterolemia,
impaired weight gain, and abnormal bone development.
Homozygous mice had markedly elevated serum T4 and
TSH and a much more severe phenotype. It thus appears
that the mutant TR has dominant negative activity on TR
function in this mouse model of RTH. It also will be
interesting to compare the expression of target genes in
these mice with the TR␣ o/o//TR␤ ⫺/⫺ knockout mice in
the absence of TH, as the latter mice do not have TRs to
mediate basal repression. Recently, Wondisford and colleagues (191a) have generated “knock-in” mice expressing mutant TR␤, and these mice have abnormal cerebellar
development and function, as well as learning deficits.
Finally, Weiss et al. (550) have shown that loss of a
coactivator can also lead to mild RTH. Using SRC-1
knockout mice that previously had been shown to have
have some resistance to steroid hormones in reproductive
tissues, they found that the knockout mice had mildy
Volume 81
July 2001
5.
6.
7.
8.
9.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
transgenic mice into thyroid hormone resistance and the regulation
of thyrotropin. J Clin Invest 103: 271–279, 1999.
ABU EO, BORD S, HORNER A, CHATTERJEE VK, AND COMPSTON JE. The
expression of thyroid hormone receptors in human bone. Bone 21:
137–142, 1997.
ABU EO, HORNER A, TETI A, CHATTERJEE VK, AND COMPSTON JE. The
localization of thyroid hormone receptor mRNAs in human bone.
Thyroid 10: 287–293, 2000.
ADAMS M, MATHEWS C, COLLINGWOOD TN, TONE Y, BECK-PECCOZ P, AND
CHATTERJEE VK. Genetic analyses of 29 kindreds with generalized
and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor b gene.
J Clin Invest 904: 506 –515, 1994.
AILHAUD G, GRIMALDI P, AND NEGREL R. Cellular and molecular
aspects of adipose tissue development. Annu Rev Nutr 12: 207–233,
1992.
ALLAIN TJ, CHAMBERS TJ, FLANAGAN AM, AND MCGREGOR AM. Triiodothyronine stimulates rat osteoclastic bone resoprtion by an
indirect effect. J Endocrinol 133: 327–331, 1992.
ALLAIN TJ AND MCGREGOR AM. Thyroid hormones and bone. J
Endocrinol 139: 9 –18, 1993.
ALLAIN TJ, YEN PM, FLANAGAN AM, AND MCGREGOR AM. The isoformspecific expression of the tri-iodothyronine receptor in osteoblasts
and osteoclasts. Eur J Clin Invest 26: 418 – 425, 1996.
ALLAND L, MUHLE R, HOU H JR, POTES J, CHIN L, SCHREIBER-AGUS N,
AND DEPINHO RA. Role for N-CoR and histone deacetylase in Sin3mediated transcriptional repression. Nature 387: 49 –55, 1997.
ALVAREZ-DOLADO M, GONZALEZ-SANCHO JM, BERNAL J, AND MUNOZ A.
Developmental expression of the tenascin-C is altered by hypothyroidism in the rat brain. Neuroscience 84: 309 –322, 1998.
ALVAREZ-DOLADO M, RUIZ M, DEL RIO JA, ALCANTARA S, BURGAYA F,
SHELDON M, NAKAJIMA K, BERNAL J, HOWELL BW, CURRAN T, SORIANO
E, AND MUNOZ A. Thyroid hormone regulates reelin and dab1 expression during brain development. J Neurosci 19: 6979 – 6993,
1999.
ANDERSON GW, LARSON RJ, OAS DR, SANDHOFER CR, SCHWARTZ HL,
MARIASH CN, AND OPPENHEIMER JH. Chicken ovalbumin upstream
promoter-transcription factor (COUP-TF) modulates expression of
the Purkinje cell protein-2 gene. A potential role for COUP-TF in
repressing premature thyroid hormone action in the developing
brain. J Biol Chem 273: 16391–16399, 1998.
ANDERSSON ML, NORDSTROM K, DEMEZUK S, HARBERS M, AND
VENNSTROM B. Thyroid hormone alters the DNA binding properties
of chicken thyroid hormone receptors a and b. Nucleic Acids Res
20: 4803– 4870, 1992.
ANDO S, SARLIS NJ, KRISHNAN J, FENG X, OLDFIELD E, AND YEN PM.
Somatic mutation or aberrant alternative-splicing of thyroid hormone receptor ␤ can cause resistance to thyroid hormone in TSHsecreting pituitary adenomas. Proc Annu Meet Endocrine Soc 2001
Denver CO.
ANZICK SL, KONONEN J, WALKER RL, AZORSA DO, TANNER MM, GUAN
XY, SAUTER G, KALLIONIEMI OP, TRENT JM, AND MELTZER PS. AIB1, a
steroid receptor coactivator amplified in breast and ovarian cancer.
Science 277: 965–968, 1997.
ASHIZAWA K, MCPHIE P, LIN KH, AND CHENG SY. An in vitro novel
mechanism of regulating the activity of pyruvate kinase M2 by
thyroid hormone and fructose 1,6 bisphosphate. Biochemistry 30:
7105–7111, 1991.
AU-FLIEGNER M, HELMER E, CASANOVA J, RAAKA BM, AND SAMUELS HH.
The conserved ninth C-terminal heptad in thyroid hormone and
retinoic acid receptors mediates diverse responses by affecting
heterodimer but not homodimer formation. Mol Cell Biol 13: 5725–
5737, 1993.
BALASUBRAMANIAN B AND MOORE DD. Interaction of thyroid hormone
receptor with chromatin remodeling proteins (Abstract). In: Nuclear Receptors 2000, Keystone Symposium. Steamboat Springs,
CO: Keystone, 2000, p. 403.
BALKMAN C, OJAMAA K, AND KLEIN I. Time course of the in vivo effects
of thyroid hormone on cardiac gene expression. Endocrinology
130: 2001–2006, 1992.
BALL SG, IKEDA M, AND CHIN WW. Deletion of the thyroid hormone
beta1 receptor increases basal and triiodothyronine-induced
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
1127
growth hormone messenger ribonucleic acid in GH3 cells. Endocrinology 138: 3125–3132, 1997.
BANIAHMAD A, HA I, REINBERG D, TSAI MJ, TSAI SY, AND O’MALLEY BW.
Interaction of human thyroid hormone receptor b with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. Proc Natl Acad Sci USA 90: 8832– 8836,
1993.
BANIAHMAD A, KOHNE AC, AND RENKAWITZ R. A transferable silencing
domain is present in the thyroid hormone receptor, in the v-erbA
oncogene product, and in the retinoic acid receptor. EMBO J 11:
1015–1023, 1992.
BANIAHMAD A, LENG X, BURRIS TP, TSAI SY, TSAI MJ, AND O’MALLEY
BW. The tau 4 activation domain of the thyroid hormone receptor
is required for release of a putative corepressor(s) necessary for
transcriptional silencing. Mol Cell Biol 15: 76 – 86, 1995.
BANIAHMAD A, TSAI SY, O’MALLEY BW, AND TSAI MJ. Kindred S thyroid
hormone receptor is an active and constitutive silencer and a
repressor for thyroid hormone and retinoic acid responses. Proc
Natl Acad Sci USA 89: 10633–10637, 1992.
BANKER DE AND EISENMAN RN. Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis.
Mol Cell Biol 13: 7540 –7552, 1993.
BARAN DT AND BRAVERMAN LE. Thyroid hormones and bone mass.
J Clin Endocrinol Metab 72: 1182–1183, 1991.
BARETTINO D, VIVANCO MMR, AND STUNNENBERG HG. Characterization
of the ligand-dependent transactivation domain of thyroid hormone
receptor. EMBO J 13: 3039 –3049, 1994.
BARLOW C, MEISTER B, LARDELLI M, LENDAHL U, AND VENNSTROM B.
Thyroid abnormalities and hepatocellular carcinoma in mice transgenic for v-erbA. EMBO J 13: 4241– 4250, 1994.
BASSI MT, RAMESAR RS, CACIOTTI B, WINSHIP IM, DE GRANDI A, RIBONI
M, TOWNES PL, BEIGHTON P, BALLABIO A, AND BORSANI G. X-linked
late-onset sensorineural deafness caused by a deletion involving
OA1 and a novel gene containing WD-40 repeats. Am J Hum Genet
64: 1604 –1616, 1999.
BAUMANN CT, MARUVADA P, HAGER GL, AND YEN PM. Nuclear-cytoplasmic shuttling by thyroid hormone receptors: multiple protein
interactions are required for nuclear retention. J Biol Chem 276:
11237–11245, 2001.
BEATO M, HERRLICH P, AND SCHUTZ G. Steroid hormone receptors:
many actors in search of a plot. Cell 83: 851– 857, 1995.
BECK-PECCOZ P AND CHATTERJEE VK. The variable clinical phenotype
in thyroid hormone resistance syndrome. Thyroid 4: 225–232, 1994.
BEHR M AND LOOS U. A point mutation (Ala229 to Thr) in the hinge
domain of the c-erbA beta thyroid hormone receptor gene in a
family with generalized thyroid hormone resistance. Mol Endocrinol 6: 1119 –1126, 1992.
BERNAL J. Iodine and brain development. Biofactors 10: 271–276,
1999.
BHAT MK, ASHIZAWA K, AND CHENG SY. Phosphorylation enhances
the target gene sequence-dependent dimerization of thyroid hormone receptor with retinoid X receptor. Proc Natl Acad Sci USA
91: 7927–7931, 1994.
BIGLER J AND EISENMAN RN. Novel location and function of a thyroid
hormone response element. EMBO J 14: 5710 –5723, 1995.
BIGLER J, HOKANSON W, AND EISENMAN RN. Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated
forms of the receptor. Mol Cell Biol 12: 2406 –2417, 1992.
BLANCO JC, MINUCCI S, LU J, YANG XJ, WALKER KK, CHEN H, EVANS
RM, NAKATANI Y, AND OZATO K. The histone acetylase PCAF is a
nuclear receptor coactivator. Genes Dev 12: 1638 –1651, 1998.
BLENNEMANN B, LEAHY P, KIM TS, AND FREAKE HC. Tissue-specific
regulation of lipogenic mRNAs by thyroid hormone. Mol Cell Endocrinol 110: 1– 8, 1995.
BODENNER DL, MROCZYNSKI MA, WEINTRAUB BD, RADOVICK S, AND
WONDISFORD FE. A detailed functional and structural analysis of a
major thyroid hormone inhibitory element in the human thyrotropin beta-subunit gene. J Biol Chem 266: 21666 –21673, 1991.
BOGAZZI F, HUDSON LD, AND NIKODEM VM. A novel heterodimerization partner for thyroid hormone receptor. Peroxisome proliferator-activated receptor. J Biol Chem 269: 11683–11686, 1994.
BOURGUET W, RUFF M, CHAMBON P, GRONEMEYER H, AND MORAS D.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
10.
THYROID HORMONE ACTION
1128
47.
48.
49.
50.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature 375: 377–382, 1995.
BRADLEY DJ, TOWLE HC, AND YOUNG WS. Spatial and temporal expression of a- and b-thyroid hormone receptor mRNAs, including
the b2-subtype, in the developing mammalian system. J Neurosci
12: 2288 –2302, 1992.
BRADLEY DJ, TOWLE HC, AND YOUNG WS. Alpha and beta thyroid
hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in
vivo. Proc Natl Acad Sci USA 91: 439 – 443, 1994.
BRANCO M, RIBEIRO M, NEGRAO N, AND BIANCO AC. 3,5,3⬘-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity. Am J Physiol Endocrinol Metab 276: E179 –E187,
1999.
BRAVERMAN LE, INGBAR SH, AND STERLING K. Conversion of thyroxine
(T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin
Invest 49: 855– 864, 1970.
BREEN JJ, HICKOK NJ, AND GURR JA. The rat TSH␤ gene contains
distinct response elements for regulation by retinoids and thyroid
hormone. Mol Cell Endocrinol 131: 137–146, 1997.
BRENT GA. The molecular basis of thyroid hormone action. N Engl
J Med 331: 847– 853, 1994.
BRENT GA, DUNN MK, HARNEY JW, GULICK T, LARSEN PR, AND MOORE
DD. Thyroid hormone aporeceptor represses T3-inducible promoters and blocks activity of the retinoic acid receptor. New Biologist
1: 329 –336, 1989.
BRENT GA, HARNEY JW, CHEN Y, WARNE RL, MOORE DD, AND LARSEN
PR. Mutations of the rat growth hormone promoter which increase
and decrease response to thyroid hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element. Mol Endocrinol 3: 1996 –
2004, 1989.
BRENT GA, HARNEY JW, MOORE DD, AND LARSEN PR. Multihormonal
regulation of the human, rat, and bovine growth hormone promoters: differential effects of 3⬘,5⬘-cyclic adenosine monophosphate,
thyroid hormone, and glucocorticoids. Mol Endocrinol 2: 792–798,
1988.
BRENT GA, WILLIAMS GR, HARNEY JW, FORMAN BM, SAMUELS HH,
MOORE DD, AND LARSEN PR. Capacity for cooperative binding of
thyroid hormone (T3) receptor dimers defines wild type T3 response elements. Mol Endocrinol 6: 502–514, 1992.
BRENT GA, WILLIAMS GR, HARNEY JW, FORMAN BM, SAMUELS HH,
MOORE DD, AND LARSEN PR. Effects of varying the position of
thyroid hormone response elements within the rat growth hormone
promoter: implications for positive and negative regulation by
3,5,3⬘-triiodothyronine. Mol Endocrinol 5: 542–548, 1991.
BRITTO JM, FENTON AJ, HOLLOWAY WR, AND NICHOLSON GC. Osteoblasts mediate thyroid hormone stimulation of osteoclastic bone
resorption. Endocrinology 134: 169 –176, 1994.
BROWN DD, WANG Z, KANAMORI A, ELICEIRI B, FURLOW JD, AND
SCHWARTZMAN R. Amphibian metamorphoses: a complex program of
gene expression changes controlled by the thyroid hormone. Rec
Prog Horm Res 50: 309 –315, 1995.
BRUCKER-DAVIS F, SKARULIS MC, GRACE MB, BENICHOU J, HAUSER P,
WIGGS E, AND WEINTRAUB BD. Genetic and clinical features of 42
kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med 123: 572–583,
1995.
BRZOZOWSKI AM, PIKE AC, DAUTER Z, HUBBARD RE, BONN T, ENGSTROM
O, OHMAN L, GREENE GL, GUSTAFSSON JA, AND CARLQUIST M. Molecular basis of agonism and antagonism in the oestrogen receptor.
Nature 389: 753–758, 1997.
BURATOWSKI S. The basics of basal transcription by RNA polymerase
II. Cell 77: 1–3, 1994.
BURNSIDE J, DARLING DS, AND CHIN WW. A nuclear factor that enhances binding of thyroid hormone receptors to thyroid hormone
response elements. J Biol Chem 265: 2500 –2504, 1990.
BURRIS TP, NAWAZ Z, TSAI MJ, AND O’MALLEY BW. A nuclear hormone
receptor-associated protein that inhibits transactivation by the thyroid hormone and retinoic acid receptors. Proc Natl Acad Sci USA
92: 9525–9529, 1995.
BUTT TR AND WALFISH PG. Human nuclear receptor heterodimers:
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
Volume 81
opportunities for detecting targets of transcriptional regulation
using yeast. Gene Exp 5: 255–268, 1996.
CAIRA F, ANTONSON P, PELTO-HUIKKO M, TREUTER E, AND GUSTAFSSON
JA. Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J Biol Chem 275: 5308 –5317, 2000.
CAIRNS BR, LEVINSON RS, YAMAMOTO KR, AND KORNBERG RD. Essential
role of Swp73p in the function of yeast Swi/Snf complex. Genes Dev
10: 2131–2144, 1996.
CALVO R, OBREGON MJ, RUIZ DE ONA C, ESCOBAR DEL REY F, AND
MORREALE DE ESCOBAR G. Congenital hypothyroidism, as studied in
rats. Crucial role of maternal thyroxine but not of 3,5,3⬘-triiodothyronine in the protection of the fetal brain. J Clin Invest 86: 889 –
899, 1990.
CARRE JL, DEMERENS C, RODRIGUEZ-PENA A, FLOCH HH, VINCENDON G,
AND SARLIEVE LL. Thyroid hormone receptor isoforms are sequentially expressed in oligodendrocyte lineage cells during rat cerebral
development. J Neurosci Res 54: 584 –594, 1998.
CASAS F, ROCHARD P, RODIER A, CASSAR-MALEK I, MARCHAL-VICTORION
S, WIESNER RJ, CABELLO G, AND WRUTNIAK C. A variant form of the
nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role
in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19:
7913–7924, 1999.
CATTINI PA, ANDERSON TR, BAXTER JD, MELLON P, AND EBERHARDT NL.
The human growth hormone gene is negatively regulated by triiodothyronine when transfected into rat pituitary tumor cells.
J Biol Chem 261: 13367–13372, 1986.
CAVAILLES V, DAUVOIS S, L’HORSET F, LOPEZ G, HOARE S, KUSHNER PJ,
AND PARKER MG. Nuclear factor RIP140 modulates transcriptional
activation by the estrogen receptor. EMBO J. 14: 3741–3751, 1995.
CHAKRAVARTI D, LAMORTE VJ, NELSON MC, NAKAJIMA T, SCHULMAN IG,
JUGUILON HJ, MONTMINY M, AND EVANS RM. Role of CBP/P300 in
nuclear receptor signaling. Nature 383: 99 –102, 1996.
CHANG KH, CHEN Y, CHEN TT, CHOU WH, CHEN PL, MA YY, YANG-FENG
TL, LENG X, TSAI MJ, O’MALLEY BW, AND LEE WH. A thyroid hormone
receptor coactivator negatively regulated by the retinoblastoma
protein. Proc Natl Acad Sci USA 94: 9040 –9045, 1997.
CHASSANDE O, FRAICHARD A, GAUTHIER K, FLAMANT F, LEGRAND C,
SAVATIER P, LAUDET V, AND SAMARUT J. Identification of transcripts
initiated from an internal promoter in the c-erbA alpha locus that
encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities. Mol Endocrinol 11: 1278 –1290, 1997.
CHATTERJEE VK, LEE JK, RENTOUMIS A, AND JAMESON JL. Negative
regulation of the thyroid-stimulating hormone alpha gene by thyroid hormone: receptor interaction adjacent to the TATA box. Proc
Natl Acad Sci USA 86: 9114 –9118, 1989.
CHATTERJEE VK, NAGAYA T, MADISON LM, DATTA S, RENTOUMIS A, AND
JAMESON JL. Thyroid hormone resistance: inhibition of normal receptor function by mutant thyroid hormone receptors. J Clin Invest 87: 1977–1984, 1991.
CHATTERJEE VK AND TATA JR. Thyroid hormone receptors and their
role in development. Cancer Survey 14: 147–167, 1992.
CHAWLA A AND LAZAR MA. Induction of Rev-erbA alpha, an orphan
receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem
268: 16265–16269, 1993.
CHEN D, MA H, HONG H, KOH SS, HUANG SM, SCHURTER BT, ASWAD
DW, AND STALLCUP MR. Regulation of transcription by a protein
methyltransferase. Science 284: 2174 –2177, 1999.
CHEN H, LIN RJ, SCHILTZ RL, CHAKRAVARTI D, NASH A, NAGY L, PRIVALSKY ML, NAKATANI Y, AND EVANS RM. Nuclear receptor coactivator
ACTR is a novel histone acetyltransferase and forms a multimeric
activation complex with P/CAF and CBP/p300. Cell 90: 569 –580,
1997.
CHEN JD AND EVANS RM. A transcriptional corepressor that interacts
with nuclear hormone receptors. Nature 377: 454 – 457, 1995.
CHENG SY. Multiple mechanisms for regulation of the transcriptional activity of tyroid hormone receptors. Rev Endocr Metabolic
Disorders 1/2: 9 –18, 2000.
CHENG SY, GONG QH, PARKISON C, ROBINSON EA, APPELLA E, MERLINO
GT, AND PASTAN I. The nucleotide sequence of a human cellular
thyroid hormone binding protein present in endoplasmic reticulum.
J Biol Chem 262: 11221–11227, 1987.
CHIELLINI G, APRILETTI JW, AL YOSHIHARA H, BAXTER JD, RIBEIRO RC,
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
51.
PAUL M. YEN
July 2001
THYROID HORMONE ACTION
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
ceptor is translated in the DNA binding state and is not associated
with hsp90. J Biol Chem 265: 3615–3618, 1990.
DAMM K, THOMPSON CC, AND EVANS RM. Protein encoded by v-erbA
functions as a thyroid-hormone receptor antagonist. Nature 339:
593–597, 1989.
DANIELIAN PS, WHITE R, LEES JA, AND PARKER MG. Identification of a
conserved region required for hormone dependent transcriptional
activation by steroid hormone receptors. EMBO J 11: 1025–1033,
1992.
DANIELSON M, HINCK L, AND RINGOLD G. Two amino acids within the
knuckle of the first zinc finger specify DNA response element
activation by the glucocorticoid receptor. Cell 57: 1131–1138, 1989.
DARIMONT BD, WAGNER RL, APRILETTI JW, STALLCUP MR, KUSHNER PJ,
BAXTER JD, FLETTERICK RJ, AND YAMAMOTO KR. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev 12:
3343–3356, 1998.
DARLING DS, BURNSIDE J, AND CHIN WW. Binding of thyroid hormone
receptors to the rat thyrotropin-beta gene. Mol Endocrinol 3: 1359 –
1368, 1989.
DARLING DS, CARTER RL, YEN PM, WELBORN JM, CHIN WW, AND
UMEDA PK. Different dimerization activities of a and b thyroid
hormone receptor isoforms. J Biol Chem 268: 10221–10227, 1993.
DARRAS VM, HUME R, AND VISSER TJ. Regulation of thyroid hormone
metabolism during fetal development. Mol Cell Endocrinol 151:
37– 47, 1999.
DAVIDSON NO, CARLOS RC, AND LUKASZEWICZ AM. Apolipoprotein B
mRNA editing is modulated by thyroid hormone analogs but not
growth hormone administration in the rat. Mol Endocrinol 4: 779 –
785, 1990.
DAVIS FB, DAVIS PJ, AND BLAS SD. Role of calmodulin in thyroid
hormone stimulation of in vitro human erythrocyte Ca2⫹-ATPase
activity. J Clin Invest 71: 579 –586, 1983.
DAVIS FB, SHIH Y, LIN A, AND DAVIS PJ. Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. Proc
Endocr Soc Meet 81st San Diego CA 1999, p. OR7–1.
DAVIS KD AND LAZAR MA. Selective antagonism of thyroid hormone
action by retinoic acid. J Biol Chem 267: 3185–3189, 1992.
DAVIS PJ AND BLAS SD. In vitro stimulation of human red blood cell
Ca2⫹-ATPase by thyroid hormone. Biochem Biophys Res Commun
99: 1073–1080, 1981.
DAVIS PJ AND DAVIS FB. Nongenomic actions of thyroid hormone.
Thyroid 6: 497–504, 1996.
DE VIJLDER JJ, RIS-STALPERS C, AND VULSMA T. Inborn errors of
thyroid hormone biosynthesis. Exp Clin Endocrinol Diabetes 4:
32–37, 1997.
DEY A, MINUCCI S, AND OZATO K. Ligand-dependent occupancy of the
reinoic acid receptor beta 2 promoter in vivo. Mol Cell Biol 14:
8191– 8201, 1994.
DIAMOND MI, MINER JM, YOSHINAGA SK, AND YAMAMOTO KR. Transcription factor interactions: selectors of positive or negative regulation
from a single DNA element. Science 249: 1266 –1272, 1990.
DILLMANN WH. Biochemical basis of thyroid hormone action in the
heart. Am J Med 88: 626 – 630, 1990.
DILLMANN WH. Thyroid hormone action and cardiac contractility—a
complex affair. Endocrinology 137: 799 – 801, 1996.
DING XF, ANDERSON CM, MA H, HONG H, UHT RM, KUSHNER PJ, AND
STALLCUP MR. Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid
receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol 12: 302–313, 1998.
DOZIN B, CAHNMANN HJ, AND NIKODEM VM. Identification of thyroid
hormone receptors in rat liver nuclei by photoafffinity labeling with
L-thyroxine and triiodothyronine. Biochemistry 24: 5197–5202,
1985.
ENGLER D AND BURGER AG. The deiodination of the iodothyronines
and of their derivatives in man. Endocr Rev 5: 151–184, 1984.
ESCOBAR-MORREALE HF, ESCOBAR DEL REY F, AND MORREALE DE ESCOBAR G. Thyroid hormones influence serum leptin concentrations in
the rat. Endocrinology 138: 4485– 4488, 1997.
EVANS RM. The steroid and thyroid hormone receptor superfamily.
Science 240: 889 – 895, 1988.
FAIRCLOUGH L AND TATA JR. An immunocytochemical analysis of the
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
SCANLAN TS. A high-affinity subtype-selective agonist ligand for
the thyroid hormone receptor. Chem Biol 5: 299 –306, 1998.
87. CHILDS GV, TAUB K, JONES KE, AND CHIN WW. Triiodothyronine
receptor beta-2 messenger ribonucleic acid expression by somatotropes and thyrotropes: effect of propylthiouracil-induced hypothyroidism in rats. Endocrinology 129: 2767–2773, 1991.
88. CHIN WW, CARR FE, BURNSIDE J, AND DARLING DS. Thyroid hormone
regulation of thyrotropin gene expression. Rec Prog Horm Res 48:
393– 414, 1993.
89. CHIN WW AND YEN PM. T3 or not T3—the slings and arrows of
outrageous TR function. Endocrinology 137: 387–388, 1996.
90. CHOMCZYNSKI P, SOSZYNSKI PA, AND FROHMAN LA. Stimulatory effect
of thyroid hormone on growth hormone gene expression in a
human pituitary cell line. J Clin Endocrinol Metab 77: 281–285,
1993.
91. CLARET X, ANTAKLY T, KARIN M, AND SAATCIOGLU F. A shift in the
ligand responsiveness of thyroid hormone receptor a induced by
heterodimerization with retinoid X receptor a. Mol Cell Biol 16:
219 –227, 1996.
92. CLIFTON-BLIGH RJ, DE ZEGHER F, WAGNER RL, COLLINGWOOD TN, FRANCOIS I, VAN HELVOIRT M, FLETTERICK RJ, AND CHATTERJEE VK. A novel
TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative
transcriptional regulation. Mol Endocrinol 12: 609 – 621, 1998.
93. COHEN RN, WONDISFORD FE, AND HOLLENBERG AN. Two separate
NCoR (nuclear receptor corepressor) interaction domains mediate
corepressor action on thyroid hormone response elements. Mol
Endocrinol 12: 1567–1581, 1998.
94. COLLINGWOOD TN, ADAMS N, AND CHATTERJEE VK. Spectrum of transcriptional, dimerization, and dominant negative properties of
twenty different mutant thyroid hormone beta-receptors in thyroid
hormone resistance syndrome. Mol Endocrinol 8: 1261–1277, 1994.
95. COLLINGWOOD TN, BUTLER A, TONE Y, CLIFTON-BLIGH RJ, PARKER MG,
AND CHATTERJEE VK. Thyroid hormone-mediated enhancement of
heterodimer formation between thyroid hormone receptor beta
and retinoid X receptor. J Biol Chem 272: 13060 –13065, 1997.
96. COLLINGWOOD TN, RAJANAYAGAM O, ADAMS M, WAGNER R, CAVAILLES V,
KALKHOVEN E, MATHEWS C, NYSTROM E, STENLOF K, LINDSTEDT G,
TISELL L, FLETTERICK RJ, PARKER MG, AND CHATTERJEE VK. A natural
transactivation mutation in the thyroid hormone b receptor: impaired interaction with putative transcriptional mediators. Proc
Natl Acad Sci USA 94: 248 –253, 1997.
97. COLLINGWOOD TN, WAGNER R, MATTHEWS CH, CLIFTON-BLIGH RJ, GURNELL M, RAJANAYAGAM O, AGOSTINI M, FLETTERICK RJ, BECK-PECCOZ P,
REINHARDT W, BINDER G, RANKE MB, HERMUS A, HESCH RD, LAZARUS
J, NEWRICK P, PARFITT V, RAGGATT P, DE ZEGHER F, AND CHATTERJEE
VK. A role for helix 3 of the TRbeta ligand-binding domain in
coactivator recruitment identified by characterization of a third
cluster of mutations in resistance to thyroid hormone. EMBO J 17:
4760 – 4770, 1998.
97a.COMMITTEE OF THE CLINICAL SOCIETY OF LONDON. Report of a committee of the Clinical Society of London nominated December 1883, to
investigate the subject of myxoedema. Trans Clin Soc Lond 21
Suppl: 1888.
98. COOK CB, KAKUCSKA I, LECHAN RM, AND KOENIG RJ. Expression of
thyroid hormone receptor b2 in rat hypothalamus. Endocrinology
130: 1077–1079, 1992.
99. COONEY AJ, TSAI SY, O’MALLEY BW, AND TSAI MJ. Chicken ovalbumin
upstream promoter transcription factor (COUP-TF) dimers bind to
different GGTCA response elements, allowing COUP-TF to repress
hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. Mol Cell Biol 12: 4153– 4163, 1992.
100. CORBETTA S, ENGLARO P, GIAMBONA S, PERSANI L, BLUM WF, AND
BECK-PECCOZ P. Lack of effects of circulating thyroid hormone
levels on serum leptin concentrations. Eur J Endocrinol 137: 659 –
663, 1997.
101. CREW CD AND SPINDLER SR. Thyroid hormone regulation of the
transfected rat growth hormone promoter activity. J Biol Chem
261: 5018 –5022, 1986.
102. DAI G, LEVY O, AND CARRASCO N. Cloning and characterization of the
thyroid iodide transporter. Nature 379: 458 – 460, 1996.
103. DALMAN FC, KOENIG RJ, PERDEW GH, MASSA E, AND PRATT WB. In
contrast to the glucocorticoid receptor, the thyroid hormone reAND
1129
1130
128.
129.
130.
131.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
expression of thyroid hormone receptor alpha and beta proteins
during natural and thyroid hormone-induced metamorphosis in
Xenopus. Dev Growth Differ 39: 273–283, 1997.
FALCONE M, MIYAMOTO T, FIERRO-RENOY F, MACCHIA E, AND DEGROOT
LJ. Antipeptide polyclonal antibodies specifically recognize each
human thyroid hormone receptor isoform. Endocrinology 131:
2419 –2429, 1992.
FARSETTI A, DESVERGNE B, HALLENBECK P, ROBBINS J, AND NIKODEM
VM. Characterization of myelin basic protein thyroid hormone
response element and its function in the context of native and
heterologous promoter. J Biol Chem 267: 15784 –15788, 1992.
FARSETTI A, MITSUHASHI T, DESVERGNE B, ROBBINS J, AND NIKODEM VM.
Molecular basis of thyroid hormone regulation of myelin basic
protein gene expression in rodent brain. J Biol Chem 266: 23226 –
23232, 1991.
FARWELL AP, DIBENEDETTO DJ, AND LEONARD JL. Thyroxine targets
different pathways of internalization of type II iodothyronine 5⬘deiodinase in astrocytes. J Biol Chem 268: 50 –55, 1993.
FARWELL AP, SAFRAN M, DUBORD S, AND LEONARD JL. Degradation and
recycling of the substrate-binding subunit of type II iodothyronine
5⬘deiodonase in astrocytes. J Biol Chem 271: 16369 –16374, 1996.
FARWELL AP, TRANTER MP, AND LEONARD JL. Thyroxine-dependent
regulation of integrin-laminin interactions in astrocytes. Endocrinology 136: 3909 –3915, 1995.
FENG W, RIBEIRO RC, WAGNER RL, NGUYEN H, APRILETTI JW, FLETTERICK RJ, BAXTER JD, KUSHNER PJ, AND WEST BL. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280: 1747–1749, 1998.
FENG X, JIANG Y, MELTZER P, AND YEN PM. Transgenic targeting of a
dominant negative co-repressor to liver blocks basal repression by
the thyroid hormone receptor and increases cell proliferation. J
Biol Chem. In press.
FENG X, JIANG Y, MELTZER P, AND YEN PM. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA
microarray. Mol Endocrinol 14: 947–955, 2000.
FLAMANT F AND SAMARUT J. Involvement of thyroid hormone and its
alpha receptor in avian neurulation. Dev Biol 197: 1–11, 1998.
FLINK IL, EDWARDS JG, BAHL C, LIEW JJ, SOLE M, AND MORKIN E.
Characterization of a strong positive cis-acting element of the
human b myosin heavy chain gene in fetal rat heart cells. J Biol
Chem 267: 9917–9924, 1992.
FLORES-DELGADO G, MARSCH-MORENO M, AND KURI-HARCUCH W. Thyroid hormone stimulates adipocyte differentiation of 3T3 cells. Mol
Cell Biochem 76: 35– 43, 1987.
FLYNN TR, HOLLENBERG AN, COHEN O, MENKE JB, USALA SJ, TOLLIN S,
HEGARTY MK, AND WONDISFORD FE. A novel C-terminal domain in the
thyroid hormone receptor selectively mediates thyroid hormone
inhibition. J Biol Chem 269: 32713–32716, 1994.
FONDELL JD, GE J, AND ROEDER RG. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc
Natl Acad Sci USA 93: 8329 – 8333, 1996.
FONDELL JD, ROY AL, AND ROEDER RG. Unliganded thyroid hormone
receptor inhibits formation of a functional preinitiation complex:
implications for active repression. Genes Dev 7: 1400 –1410, 1993.
FORCE WR AND SPINDLER SR. 3,5,3⬘-L-Triiodothyronine (thyroid hormone)-induced protein-DNA interactions in the thyroid hormone
response elements and cell type-specific elements of the rat growth
hormone gene revealed by in vivo dimethyl sulfate footprinting.
J Biol Chem 269: 9682–9686, 1994.
FORMAN BM, CASANOVA J, RAAKA BM, GHYSDAEL J, AND SAMUELS HH.
Half-site spacing and orientation determines whether thyroid hormone and retinoic acid receptor and related factors bind to DNA
response elements as monomers, homodimers, or heterodimers.
Mol Endocrinol 6: 429 – 442, 1992.
FORMAN BM AND SAMUELS HH. Interactions among a subfamily of
nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol 4: 1293–1301, 1990.
FORMAN BM, TOTONOZ P, CHEN J, BRUN RP, SPIEGELMAN BM, AND
EVANS RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the
adipocyte determination factor PPAR gamma. Cell 83: 803– 812,
1995.
FORMAN BM, UMESONO K, CHEN J, AND EVANS RM. Unique response
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
Volume 81
pathways are established by allosteric interactions among nuclear
hormone receptors. Cell 81: 541–550, 1995.
FORMAN BM, YANG CR, STANLEY F, AND CASANOVA J. c-erbA protoncogenes mediate thyroid hormone-dependent and independent regulation of the rat growth hormone and prolactin genes. Mol Endocrinol 2: 902–911, 1988.
FORREST D, ERWAY LC, NG L, ALTSCHULER R, AND CURRAN T. Thyroid
hormone receptor beta is essential for development of auditory
function. Nat Genet 13: 354 –357, 1996.
FORREST D, HANEBUTH E, SMEYNE RJ, EVAERDS N, STEWART CL, WEHNER JM, AND CURRAN T. Recessive resistance to thyroid hormone in
mice lacking thyroid hormone receptor beta: evidence for tissuespecific modulation of receptor function. EMBO J 15: 3006 –3015,
1996.
FORREST D AND VENNSTROM B. Functions of thyroid hormone receptors in mice. Thyroid 10: 41–52, 2000.
FRAICHARD A, CHASSANDE O, PLATEROTI M, ROUX JP, TROUILLAS J,
DEHAY C, LEGRAND C, GAUTHIER K, KEDINGER M, MALAVAL L, ROUSSET
B, AND SAMARUT J. The T3R alpha gene encoding a thyroid hormone
receptor is essential for postnatal development and thyroid hormone production. EMBO J 16: 4412– 4420, 1997.
FREEDMAN LP, ARCE V, AND FERNANDEZ RP. DNA sequences that act
as high affinity targets for the vitamin D3 receptor in the absence of
the retinoid X receptor. Mol Endocrinol 8: 265–273, 1994.
FRIESEMA EC, DOCTER R, MOERINGS EP, STIEGER B, HAGENBUCH B,
MEIER PJ, KRENNING EP, HENNEMANN G, AND VISSER TJ. Identification
of thyroid hormone transporters. Biochem Biophys Res Commun
254: 497–501, 1999.
GARCIA-FERNANDEZ LF, RAUSELL E, URADE Y, HAYAISHI O, BERNAL J,
AND MUNOZ A. Hypothyroidism alters the expression of prostaglandin D2 synthase/beta trace in specific areas of the developing rat
brain. Eur J Neurosci 9: 1566 –1573, 1997.
GARCIA-VILLALBA P, JIMENEZ-LARA AM, AND ARANDA A. Vitamin D
interferes with transactivation of the growth hormone gene by
thyroid hormone and retinoic acid. Mol Cell Biol 16: 318 –327, 1996.
GAUTHIER K, CHASSANDE O, PLATEROTI M, ROUX JP, LEGRAND C, PAIN B,
ROUSSET B, WEISS R, TROUILLAS J, AND SAMARUT J. Different functions
for the thyroid hormone receptors TRalpha and TRbeta in the
control of thyroid hormone production and post-natal development. EMBO J 18: 623– 631, 1999.
GELMETTI V, ZHANG J, FANELLI M, MINUCCI S, PELICCI PG, AND LAZAR
MA. Aberrant recruitment of the nuclear receptor corepressorhistone deacetylase complex by the acute myeloid leukemia fusion
partner ETO. Mol Cell Biol 18: 7185–7191, 1998.
GHARBI-CHIHI J, FACCHINETTI T, BERGE-LEFRANC J, BONNE J, AND TORRESANI J. Triiodothyronine control of ATP-citrate lyase and malic
enzyme during differentiation of a murine preadipocyte cell line.
Horm Metab Res 23: 423– 427, 1991.
GLASS CK. Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers. Endocr Rev 15: 391–
407, 1994.
GLASS CK, HOLLOWAY JM, DEVARY OV, AND ROSENFELD MG. The
thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyrioid hormone and estrogen response elements. Cell 54: 313–323, 1988.
GLASS CK, LIPKIN SM, DEVARY OV, AND ROSENFELD MG. Positive and
negative regulation of gene transcription by a retinoic acid-thyroid
hormone receptor heterodimer. Cell 59: 697–708, 1989.
GLAUTCHNIG H, VARGA F, AND KLAUSHOFER K. Thyroid hormone and
retinoic acid induce the synthesis of insulin-like growth factorbinding protein 4 in mouse osteoblastic cells. Endocrinology 137:
281–286, 1996.
GLICK Z, WU SY, LUPIEN J, REGGIO R, BRAY GA, AND FISHER DA.
Meal-induced brown fat thermogenesis and thyroid hormone metabolism in rats. Am J Physiol Endocrinol Metab 249: E519 –E524,
1985.
GLINEUR C, BAILLY M, AND GHYSDAEL J. The c-erbA alpha-encoded
thyroid hormone receptor is phosphorylated in its amino-terminal
domain by casein kinase II. Oncogene 4: 1247–1254, 1989.
GLOSS B, SAYEN MR, TROST SU, BLUHM WF, MEYER M, SWANSON EA,
USALA SJ, AND DILLMANN WH. Altered cardiac phenotype in transgenic mice carrying the delta337 threonine thyroid hormone recep-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
132.
PAUL M. YEN
July 2001
167.
168.
169.
170.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
tor beta mutant derived from the S family. Endocrinology 140:
897–902, 1999.
GOLDBERG Y, GLINEUR C, RESQUIERE C, RICOUART A, SAP J, VENNSTROM
B, AND GHYSDAEL J. Activation of protein kinase C or cAMP-dependent protein kinase increases phosphorylation of the c-erbA-encoded thyroid hormone receptor and of the v-erbA-encoded protein. EMBO J 7: 2425–2433, 1988.
GONG DW, HE Y, KARAS M, AND REITMAN M. Uncoupling protein-3 is
a mediator of thermogenesis regulated by thyroid hormone, beta3adrenergic agonists, and leptin. J Biol Chem 272: 24129 –24132,
1997.
GONG DW, MONEMDJOU S, GAVRILOVA O, LEON LR, MARCUS-SAMUELS B,
CHOU CJ, EVERETT C, KOZAK LP, LI C, DENG C, HARPER ME, AND
REITMAN ML. Lack of obesity and normal response to fasting and
thyroid hormone in mice lacking uncoupling protein-3. J Biol
Chem. In press.
GOODRICH JA, HOEY T, THUR CJ, ADMON A, AND TJIAN R. Drosophila
TAFII40 interacts with both a VP16 activation domain and the basal
transcription factor TFIIB. Cell 75: 513–530, 1993.
GOTHE S, WANG Z, NG L, KINDBLOM JM, BARROS AC, OHLSSON C,
VENNSTROM B, AND FORREST D. Mice devoid of all known thyroid
hormone receptors are viable but exhibit disorders of the pituitarythyroid axis, growth, and bone maturation. Genes Dev 13: 1329 –
1341, 1999.
GRAFF MN, BAAS D, PUYMIRAT J, SARLIEVE LL, AND DELAUNOY JP. The
alpha and beta thyroid receptors are expressed by cultured ependymal cells. Correlation with the effect of L-3,5,3⬘-triiodothyronine on
glutamine synthetase mRNAs. Neurosci Lett 150: 174 –178, 1993.
GREEN S, KUMAR V, THEULAZ I, WAHLI W, AND CHAMBON P. The
N-terminal DNA-binding “zinc finger” of the oestrogen and glucocorticoid receptors determines target gene specificity. EMBO J
7: 3037–3044, 1988.
GREEN S, WALTER P, KUMAR V, KRUST A, BORNERT JM, ARGOS P, AND
CHAMBON P. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature 320: 134 –139, 1986.
GREENSPAN SL AND GREENSPAN FS. The effect of thyroid hormone on
skeletal integrity. Ann Intern Med 130: 750 –758, 1999.
GRIGNANI F, DE MATTEIS S, NERVI C, TOMASSONI L, GELMETTI V, CIOCE
M, FANELLI M, RUTHARDT M, FERRARA FF, ZAMIR I, SEISER C, LAZAR
MA, MINUCCI S, AND PELICCI PG. Fusion proteins of the retinoic acid
receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391: 815– 818, 1998.
GRIMALDI P, DJIAN P, NEGREL R, AND AILHAUD G. Differentiation of Ob
17 preadipocytes to adipocytes: requirment of adipose conversion
factor(s) for fat cell cluster formation. EMBO J 1: 687– 692, 1982.
GROSS J AND PITT-RIVERS R. Triiodothyronine in relation to thyroid
physiology. Rec Prog Horm Res 10: 109 –128, 1954.
GU W, MALIK S, ITO M, YUAN CX, FONDELL JD, ZHANG X, MARTINEZ E,
QIN J, AND ROEDER RG. A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol Cell 3:
97–108, 1999.
GUADANO-FERRAZ A, OBREGON MJ, ST GERMAIN DL, AND BERNAL J. The
type 2 iodothyronine deiodinase is expressed primarily in glial cells
in the neonatal rat brain. Proc Natl Acad Sci USA 94: 10391–10396,
1997.
GUISSOUMA H, GHORBEL MT, SEUGNET I, OUATAS T, AND DEMENEIX BA.
Physiological regulation of hypothalamic TRH transcription in vivo
is T3 receptor isoform specific. FASEB J 12: 1755–1764, 1998.
HADDOW JE, PALOMAKI GE, ALLAN WC, WILLIAMS JR, KNIGHT GJ,
GAGNON J, O’HEIR CE, MITCHELL ML, HERMOS RJ, WAISBREN SE, FAIX
JD, AND KLEIN RZ. Maternal thyroid deficiency during pregnancy
and subsequent neuropsychological development of the child.
N Engl J Med 341: 549 –555, 1999.
HADZIC E, DESAI-YAJNIK V, HELMER E, GUO S, WU S, KOUDINOVA N,
CASANOVA J, RAAKE BM, AND SAMUELS HH. A 10 amino acid sequence
in the N-terminal A/B domain of thyroid hormone receptor alpha is
essential for transcriptional activation and interaction with the
general transcription factor TFIIB. Mol Cell Biol 15: 4507– 4517,
1995.
HADZIC E, HABEOS I, RAAKA BM, AND SAMUELS HH. A novel multifunctional motif in the amino-terminal A/B domain of T3Ralpha modulates DNA binding and receptor dimerization. J Biol Chem 273:
10270 –10278, 1998.
1131
185. HAFNER RP, BROWN GC, AND BRAND MD. Thyroid hormone control of
state-3 respiration in isolated rat liver mitochondria. Biochem J
265: 731–734, 1990.
186. HALACHMI S, MARDEN E, MARTIN G, MACKAY H, ABBONDANZE C, AND
BROWN M. Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 264: 1455–1458,
1994.
187. HALL BL, SMIT-MCBRIDE Z, AND PRIVALSKY ML. Reconstitution of
retinoid X receptor function and combinatorial regulation of other
nuclear hormone receptors in yeast Saccharomyces cerevisiae.
Proc Natl Acad Sci USA 90: 6929 – 6933, 1993.
188. HAMMER GD, KRYLOVA I, ZHANG Y, DARIMONT BD, SIMPSON K, WEIGEL
NL, AND INGRAHAM HA. Phosphorylation of the nuclear receptor SF-1
modulates cofactor recruitment: integration of hormone signaling
in reproduction and stress. Mol Cell 3: 521–526, 1999.
189. HAO E, MENKE JB, SMITH AM, JONES C, GEFFNER ME, HERSHMAN-P
WUERTH JM, SAMUELS HH, WAYS KD, AND USALA SJ. Divergent dimerization properties of mutant TRb1 thyroid hormone receptors are
associated with different dominant negative activities. Mol Endocrinol 8: 841– 851, 1994.
190. HARDING HP AND LAZAR MA. The monomer-binding orphan receptor
Rev-Erb represses transcription as a dimer on a novel direct repeat.
Mol Cell Biol 15: 4791– 4802, 1995.
191. HARTONG R, WANG N, KUROKAWA R, LAZAR MA, GLASS CK, APRILETTI
JW, AND DILLMANN WH. Delineation of three different thyroid hormone-response elements in promoter of rat sarcoplasmic reticulum
Ca2⫹-ATPase gene. Demonstration that retinoid X receptor binds 5⬘
to thyroid hormone receptor in response element 1. J Biol Chem
269: 13021–13029, 1994.
191a.HASHIMOTO K, CURTY FH, BORGES PP, LEE CE, ABEL ED, ELMQUIST JK,
COHEN RN, AND WONDISFORD FE. An unliganded thyroid hormone
receptor causes severe neurological dysfunction. Proc Natl Acad
Sci USA 98: 3998 – 4003, 2001.
192. HAUGEN B, BROWN N, BRINKMEIER M, CAMPER S, GREENLEE L, KREZEL
W, AND CHAMBON P. Retinoid X receptor gamma deficient mice have
a biochemical phenotype consistent with mild thyroid hormone
resistance. Proc Annu Meet Endocr Soc 81st San Diego CA 1999,
p. P2– 660.
193. HAUGEN BR, BROWN NS, WOOD WM, GORDON DF, AND RIDGWAY EC.
The thyrotrope-restricted isoform of the retinoid-X receptor-gamma1 mediates 9-cis-retinoic acid suppression of thyrotropin-beta
promoter activity. Mol Endocrinol 11: 481– 489, 1997.
194. HAYASHI Y, OHMORI S, ITO T, AND SEO H. A splicing variant of Steroid
Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to
mediate thyroid hormone action. Biochem Biophys Res Commun
236: 83– 87, 1997.
195. HAYASHI Y AND REFETOFF S. A mouse model of resistance to thyroid
hormone in liver produced by somatic gene transfer of a mutant
thyroid hormone receptor. Proc Endocr Soc Meet Washington DC
1995, p. OR34 – 6.
196. HAYASHI Y, WEISS RE, SARNE DH, YEN PM, SUNTHORNTHEPVARAKUL T,
MARCOCCI C, CHIN WW, AND REFETOFF S. Do clinical manifestations
of resistance to thyroid hormone correlate with the functional
alteration of the corresponding mutant thyroid hormone-beta receptors? J Clin Endocrinol Metab 80: 3246 –3256, 1995.
197. HAYASHI Y, XIE J, WEISS RE, POHLENZ J, AND REFETOFF S. Selective
pituitary resistance to thyroid hormone produced by expression of
a mutant thyroid hormone receptor beta gene in the pituitary gland
of transgenic mice. Biochem Biophys Res Commun 245: 204 –210,
1998.
198. HAYASHI Y, YAMAMOTO M, OHMORI S, KIKUMORI T, IMAI T, FUNAHASHI H,
AND SEO H. Polymorphism of homopolymeric glutamines in coactivators for nuclear hormone receptors. Endocr J 46: 279 –284, 1999.
199. HEERY DM, KALKHOVEN E, HOARE S, AND PARKER MG. A signature
motif in transcriptional co-activators mediates binding to nuclear
receptors. Nature 387: 733–736, 1997.
200. HEINZEL T, LAVINSKY RM, MULLEN TM, SODERSTROM M, LAHERTY CD,
TORCHIA J, YANG WM, BRARD G, NGO SD, DAVIE JR, SETO E, EISENMAN
RN, ROSE DW, GLASS CK, AND ROSENFELD MG. A complex containing
N-CoR, mSin3 and histone deacetylase mediates transcriptional
repression. Nature 387: 43– 48, 1997.
201. HELMER EB, RAAKA BM, AND SAMUELS HH. Hormone-dependent and
-independent transcriptional activation by thyroid hormone recep-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
171.
THYROID HORMONE ACTION
1132
202.
203.
204.
205.
206.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
tors are mediated by different mechanisms. Endocrinology 137:
390 –399, 1996.
HEYMAN RA, MANGELSDORF DJK, DYK JA, STEIN RB, EICHELE G, EVANS
RM, AND THALLER C. 9-Cis retinoic acid is a high affinity ligand for
the retinoid X receptor. Cell 68: 397– 440, 1992.
HIMMS-HAGEN J. Brown adipose tissue thermogenesis and obesity.
Prog Lipid Res 28: 67–115, 1989.
HODIN RA, LAZAR MA, AND CHIN WW. Differential and tissue-specific
regulation of the multiple rat c-erbA mRNA species by thyroid
hormone. J Clin Invest 85: 101–105, 1990.
HODIN RA, LAZAR MA, WINTMAN BI, DARLING DS, KOENIG RJ, LARSEN
PR, MOORE DD, AND CHIN WW. Identification of a novel thyroid
hormone receptor that is pituitary-specific. Science 244: 76 –79,
1989.
HOLLENBERG AN, MONDEN T, FLYNN TR, BOERS ME, COHEN O, AND
WONDISFORD FE. The human thyrotropin-releasing hormone gene is
regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements. Mol Endocrinol 9: 540 –
550, 1995.
HOLLENBERG AN, MONDEN T, MADURA JP, LEE K, AND WONDISFORD FE.
Function of nuclear co-repressor protein on thyroid hormone response elements is regulated by the receptor A/B domain. J Biol
Chem 271: 28516 –28520, 1996.
HOLLENBERG AN, MONDEN T, AND WONDISFORD FE. Ligand-independent and -dependent functions of thyroid hormone receptor isoforms depend upon on their distinct amino terminal. J Biol Chem
270: 14272–14280, 1995.
HOLLENBERG SM, WEINBERGER C, AND ONG ES. Primary structure and
expression of a functional glucocorticoid receptor cDNA. Nature
318: 635– 641, 1985.
HONG H, KOHLI K, GARABEDIAN MJ, AND STALLCUP MR. GRIP1, a
transcriptional coactivator for the AF-2 transactivation domain of
steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 17:
2735–2744, 1997.
HORLEIN AJ, NAAR AM, HEINZEL T, TORCHIA J, GLOSS B, KUROKAWA R,
RYAN A, KAMEL Y, SODERSTROM M, GLASS CK, AND ROSENFELD MG.
Ligand-independent repression by the thyroid hormone receptor
mediated by a nuclear co-repressor. Nature 377: 397– 404, 1995.
HORWITZ KB, JACKSON TA, BAIN DL, RICHER JK, TAKIMOTO GS, AND
TUNG L. Nuclear receptor coactivators and corepressors. Mol Endocrinol 10: 1167–1177, 1996.
HTUN H, HOLTH LT, WALKER D, DAVIE JR, AND HAGER GL. Direct
visualization of the human estrogen receptor alpha reveals a role
for ligand in the nuclear distribution of the receptor. Mol Biol Cell
10: 471– 486, 1999.
HU X AND LAZAR MA. The CoRNR motif controls the recruitment of
corepressors by nuclear hormone receptors. Nature 402: 93–96,
1999.
HUANG BK, GOLDEN LA, TARJAN G, MADISON LD, AND STERN PH.
Insulin-like growth factor I production is essential for anabolic
effects of thyroid hormone in osteoblasts. J Bone Miner Res 15:
188 –197, 2000.
IKEDA M, WILCOX EC, AND CHIN WW. Thyroid hormone receptor
heterodimer on some DR4s can mediate basal repression but may
not be sufficient for transcriptional activation. Proc Endocr Soc
Meet Washington DC 1995, p. P3– 439.
ING NH, BECKMAN JM, TSAI SY, TSAI MJ, AND O’MALLEY BW. Members
of the steroid hormone receptor superfamily interact with TFIIB
(S300-II). J Biol Chem 267: 17617–17623, 1992.
ISHIKAWA Y, GENGE BR, WUTHIER RE, AND WU LN. Thyroid hormone
inhibits growth and stimulates terminal differentiation of epiphyseal growth plate chondrocytes. J Bone Miner Res 13: 1398 –1411,
1998.
ITO M, YUAN CX, MALIK S, GU W, FONDELL JD, YAMAMURA S, FU ZY,
ZHANG X, QIN J, AND ROEDER RG. Identity between TRAP and SMCC
complexes indicates novel pathways for the function of nuclear
receptors and diverse mammalian activators. Mol Cell 3: 361–370,
1999.
IZUMO S AND MAHDAVI V. Thyroid hormone receptor a isoforms
generated by alternative splicing differentially activate myosin HC
gene transcription. Nature 334: 539 –542, 1988.
JACQ X, BROU C, LUTZ Y, DAVIDSON I, CHAMBON P, AND TORA L. Human
TAFII30 is present in a distinct TFIID complex and is required for
222.
223.
224.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
Volume 81
transcriptional activation by the estrogen receptor. Cell 79: 107–
117, 1994.
JAFFIOL C, BALDET L, TORRESANI J, BISMUTH J, AND PAPACHRISTOU C. A
case of hypersensitivity to thyroid hormones with normally functioning thyroid gland and increased nuclear triiodothyronine receptors. J Endocrinol Invest 13: 839 – 845, 1990.
JAMESON JL. Mechanisms by which thyroid hormone receptor mutations cause clinical syndromes of resistance to thyroid hormone.
Thyroid 4: 485– 492, 1994.
JEANNIN E, ROBYR D, AND DESVERGNE B. Transcriptional regulatory
patterns of the myelin basic protein and malic enzyme genes by the
thyroid hormone receptors alpha1 and beta1. J Biol Chem 273:
24239 –24248, 1998.
JEKABSONS MB, GREGOIRE FM, SCHONFELD-WARDEN NA, WARDEN CH,
AND HORWITZ BA. T(3) stimulates resting metabolism and UCP-2 and
UCP-3 mRNA but not nonphosphorylating mitochondrial respiration in mice. Am J Physiol Endocrinol Metab 277: E380 –E389,
1999.
JEYAKUMAR M, TANEN MR, AND BAGCHI MK. Analysis of the functional
role of steroid receptor coactivator-1 in ligand-induced transactivation by thyroid hormone receptor. Mol Endocrinol 11: 755–767,
1997.
JOHANSSON C, GOTHE S, FORREST D, VENNSTROM B, AND THOREN P.
Cardiovascular phenotype and temperature control in mice lacking
thyroid hormone receptor-beta or both alpha1 and beta. Am J
Physiol Heart Circ Physiol 276: H2006 –H2012, 1999.
JONES KE, BRUBAKER JH, AND CHIN WW. Evidence that phosphorylation events participate in thyroid hormone action. Endocrinology
134: 543–548, 1994.
JONES KE AND CHIN WW. Differential regulation of thyroid hormone
receptor messenger ribonucleic acid levels by thyrotropin-releasing hormone. Endocrinology 128: 1763–1768, 1991.
JONES KE, YAFFE BM, AND CHIN WW. Regulation of thyroid hormone
receptor b-2 mRNA levels by retinoic acid. Mol Cell Endocrinol 91:
113–118, 1993.
JUDELSON C AND PRIVALSKY ML. DNA recognition by normal and
oncogenic thyroid hormone receptors. Unexpected diversity in
half-site specificity controlled by non-zinc finger determinants.
J Biol Chem 271: 10800 –10805, 1996.
JUGE-AUBRY CE, GORLA-BAJSZCZAK A, PERNIN A, LEMBERGER T, WAHLI
W, BURGER AG, AND MEIER CA. Peroxisome proliferator-activated
receptor mediates cross-talk with thyroid hormone receptor by
competition for retinoid X receptor. J Biol Chem 270: 18117–18122,
1995.
KAKIZAWA T, MIYAMOTO T, KANEKO A, YAJIMA H, ICHIKAWA K, AND
HASHIZUME K. Ligand-dependent heterodimerization of thyroid hormone receptor and retinoid X receptor. J Biol Chem 272: 23799 –
23804, 1997.
KAMEI Y, XU L, HEINZEL T, TORCHIA J, KUROKAWA R, GLOSS C, LIN B,
HEYMAN RA, ROSE DW, GLASS CK, AND ROSENFELD MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85: 403– 414, 1996.
KANESHIGE M, KANESHIGE K, ZHU X, DACE A, GARRETT L, CARTER TA,
KAZLAUSKAITE R, PANKRATZ DG, WYNSHAW-BORIS A, REFETOFF S, WEINTRAUB B, WILLINGHAM MC, BARLOW C, AND CHENG S. Mice with a
targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl
Acad Sci USA 97: 13209 –13214, 2000.
KATO H, FUKUDA T, PARKISON C, MCPHIE P, AND CHENG SY. Cytoplasmic thyroid hormone-binding protein is a monomer of pyruvate
kinase. Proc Natl Acad Sci USA 86: 7681–7685, 1990.
KATO S, ENDOH H, MASUHIRO Y, KITAMOTO T, UCHIYAMA S, SASAKI H,
MASUHIGE S, GOTOH Y, NISHIDA E, KAWASHIMA H, AND CHAMBON P.
Activation of the estrogen receptor through phosphorylation by
mitogen-activated protein kinase. Science 270: 1491–1494, 1995.
KATZ D, REGINATO MJ, AND LAZAR MA. Functional regulation of
thyroid hormone receptor variant TR alpha 2 by phosphorylation.
Mol Cell Biol 15: 2341–2348, 1995.
KATZ RW AND KOENIG RJ. Specificity and mechanism of thyroid
hormone induction from an octamer response element. J Biol
Chem 269: 18915–18920, 1994.
KENDALL EC. The isolation in crystalline form of the compound
containing iodine which occurs in the thyroid: its chemical nature
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
207.
PAUL M. YEN
July 2001
242.
243.
244.
245.
246.
248.
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
and physiological activity. Trans Assoc Am Physicians 30: 420 –
449, 1915.
KIM HS, CRONE DE, SPRUNG CN, TILLMAN JB, FORCE WR, CREW MD,
MOTE PL, AND SPINDLER SR. Positive and negative thyroid hormone
response elements are composed of strong and weak half-sites 10
nucleotides in length. Mol Endocrinol 6: 1489 –1501, 1992.
KIM SW, AHN IM, AND LARSEN PR. In vivo genomic footprinting of
thyroid hormone-responsive genes in pitutiary tumor cell lines. Mol
Cell Biol 16: 4465– 4477, 1996.
KING IN, DESOYZA T, CATANZARO D, AND LAVIN TN. Thyroid hormone
receptor-induced bending of specific DNA sequences is modified by
an accessory factor. J Biol Chem 268: 495–501, 1993.
KINLAW WB, CHURCH JL, HARMON J, AND MARIASH CN. Direct evidence
for a role of the “spot 14” protein in the regulation of lipid synthesis. J Biol Chem 270: 16615–16618, 1995.
KINLAW WB, TRON P, AND FRIEDMAN AS. Nuclear localization and
hepatic zonation of rat “spot 14” protein: immunohistochemical
investigation employing anti-fusion protein antibodies. Endocrinology 131: 3120 –3122, 1992.
KLAUSHOFER K, VARGA F, GLANTSCHNIG H, FRATZL-ZELMAN N, CZERWENKA E, LEIS HJ, KOLLER K, AND PETERLIK M. The regulatory role of
thyroid hormones in bone cell growth and differentiation. J Nutr
125: 1996S–2003S, 1995.
KLEIN I AND OJAMAA K. Thyrotoxicosis and the heart. Endocrinol
Metab Clin N Am 27: 51– 62, 1998.
KLEMPERER JD, KLEIN I, GOMEZ M, HELM RE, OJAMAA K, THOMAS SJ,
ISOM OW, AND KRIEGER K. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 333: 1522–1527, 1995.
KLIEWER SA, UMESONO K, NOONAN DJ, HEYMAN RA, AND EVANS RM.
Convergence of 9-cis retinoic acid and peroxisome proliferator
signaling pathways through heterodimer formation of their receptors. Nature 358: 771–774, 1992.
KLIEWER SA AND WILLSON TM. The nuclear receptor PPAR␥: bigger
than fat. Curr Opin Genet Dev 8: 576 –581, 1998.
KO L, CARDONA GR, AND CHIN WW. Thyroid hormone receptorbinding protein, an LXXLL motif-containing protein, functions as a
general coactivator. Proc Natl Acad Sci USA 97: 6212– 6217, 2000.
KOENIG RJ, LAZAR MA, HODIN RA, BRENT GA, LARSEN PR, CHIN WW,
AND MOORE DD. Inhibition of thyroid hormone action by a nonhormone binding c-erbA protein generated by alternative mRNA
splicing. Nature 337: 659 – 661, 1989.
KOENIG RJ, WARNE RL, BRENT GA, HARNEY JW, LARSEN PR, AND
MOORE DD. Isolation of a cDNA clone encoding a biologically active
thyroid hormone receptor. Proc Natl Acad Sci USA 85: 5031–5035,
1988.
KOHN LD, SHIMURA H, SHIMURA Y, HIDAKA A, GIULIANI C, NAPOLITANO
G, OHMORI M, LAGLIA G, AND SAJI M. The thyrotropin receptor. Vitam
Horm 50: 287–384, 1995.
KOHRLE J. The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability. Rev Endocr Metabolic
Disorders 1: 49 –58, 2000.
KOIBUCHI N AND CHIN W. Aberrant postnatal cerebellar development
in transgenic mouse expressing a dominant negative thyrid hormone receptor. Proc Annu Meet Endocr Soc 81d Toronto Canada
2000, p. 374.
KOIBUCHI N AND CHIN WW. ROR alpha gene expression in the
perinatal rat cerebellum: ontogeny and thyroid hormone regulation. Endocrinology 139: 2335–2341, 1998.
KOIBUCHI N, FUKUDA H, AND CHIN WW. Promoter-specific regulation
of the brain-derived neurotropic factor gene by thyroid hormone in
the developing rat cerebellum. Endocrinology 140: 3955–3961,
1999.
KOIBUCHI N, LIU Y, FUKUDA H, TAKESHITA A, YEN PM, AND CHIN WW.
ROR alpha augments thyroid hormone receptor-mediated transcriptional activation. Endocrinology 140: 1356 –1364, 1999.
KOPP P. Pendred’s syndrome and genetic defects in thyroid hormone synthesis. Rev Endocr Metabolic Disorders 1: 109 –121, 2000.
KORZUS E, TORCHIA J, ROSE DW, XU L, KUROKAWA R, MCINERNEY EM,
MULLEN TM, GLASS CK, AND ROSENFELD MG. Transcription factorspecific requirements for coactivators and their acetyltransferase
functions. Science 279: 703–707, 1998.
KRANE IM, SPINDEL ER, AND CHIN WW. Thyroid hormone decreases
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
1133
the stability and the poly(A) tract length of rat thyrotropin betasubunit messenger RNA. Mol Endocrinol 5: 469 – 475, 1991.
KRISTENSEN K, PEDERSEN SB, LANGDAHL BL, AND RICHELSEN B. Regulation of leptin by thyroid hormone in humans: studies in vivo and
in vitro. Metabolism 48: 1603–1607, 1999.
KUIPER GG, ENMARK E, PELTO-HUIKKO M, NILSSON S, AND GUSTAFSSON
JA. Cloning of a novel receptor expressed in rat prostate and ovary.
Proc Natl Acad Sci USA 93: 5925–5930, 1996.
KUROKAWA R, DIRENZO J, BOEHM M, SUGARMAN J, GLOSS B, ROSENFELD
MG, HEYMAN RA, AND GLASS CK. Regulation of retinoid signaling by
receptor polarity and allosteric control of ligand binding. Nature
371: 528 –531, 1994.
KUROKAWA R, SODERSTROM M, HORLEIN A, HALACHMI S, BROWN M,
ROSENFELD MG, AND GLASS CK. Polarity-specific activities of retinoic
acid receptors determined by a co-repressor. Nature 377: 451– 454,
1995.
KUROKAWA R, YU VC, NAAR A, KYAKUMOTO S, HAN Z, SILVERMAN S,
ROSENFELD MG, AND GLASS CK. Differential orientations of the DNAbinding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers. Gene
Dev 7: 1423–1435, 1993.
KWOK RP, LUNDBLAD JR, CHRIVIA JC, RICHARDS JP, BACHINGER HP,
BRENNAN RG, ROBERTS SG, GREEN MR, AND GOODMAN RH. Nuclear
protein CBP is a coactivator for the transcription factor CREB.
Nature 370: 223–226, 1994.
LADENSON PW, SHERMAN IS, BAUGHMAN KL, RAY PE, AND FELDMAN AM.
Reversible alterations in the myocardial gene expression in a young
man with dilated cardiomyopathy and hypothyroidism. Proc Natl
Acad Sci USA 89: 5251–5255, 1992.
LAHERTY CD, YANG WM, SUN JM, DAVIE JR, SETO E, AND EISENMAN RN.
Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89: 349 –356, 1997.
LAKATOS P, FOLDES J, HORVATH C, KISS L, TATRAI A, TAKACS I, TARJAN
G, AND STERN PH. Serum interleukin-6 and bone metabolism in
patients with thyroid function disorders. J Clin Endocrinol Metab
82: 78 – 81, 1997.
LAKATOS P AND STERN PH. Effects of cyclosporins and transforming
growth factor beta 1 on thyroid hormone action in cultured fetal rat
limb bones. Calcif Tissue Int 50: 123–128, 1992.
LAKSHMANAN M, GONCALVES E, LESSLY G, FOTI D, AND ROBINS J. The
transport of thyroxine into mouse neuroblastoma cells, NB41A3:
the effect of L-system amino acids. Endocrinology 126: 3245–3250,
1990.
LANGLOIS MF, ZANGER K, MONDEN T, SAFER JD, HOLLENBERG AN, AND
WONDISFORD FE. A unique role of the beta-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping
of a novel amino-terminal domain important for ligand-independent activation. J Biol Chem 272: 24927–33, 1997.
LANNI A, MORENO M, LOMBARDI A, AND GOGLIA F. Rapid stimulation in
vitro of rat liver cytochrome oxidase activity by 3,5-diiodo-L-thyronine and by 3,3⬘-diiodo-L-thyronine. Mol Cell Endocrinol 99: 89 –94,
1994.
LANZ RB, MCKENNA NJ, ONATE SA, ALBRECHT U, WONG J, TSAI SY, TSAI
MJ, AND O’MALLEY BW. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97: 17–27,
1999.
LANZ RB AND RUSCONI S. A conserved carboxy-terminal subdomain
is important for ligand interpretation and transactivation by nuclear receptors. Endocrinology 135: 2183–2195, 1994.
LARKIN S, MULL E, MIAO W, PITTNER R, ALBRANDT K, MOORE C, YOUNG
A, DENARO M, AND BEAUMONT K. Regulation of the third member of
the uncoupling protein family, UCP3, by cold and thyroid hormone.
Biochem Biophys Res Commun 240: 222–227, 1997.
LARSEN PR AND BERRY MJ. Nutritional and hormonal regulation of
thyroid hormone deiodinases. Annu Rev Nutr 15: 323–352, 1995.
LARSEN PR, HARNEY JW, AND MOORE DD. Sequences required for
cell-specific thyroid hormone regulation of rat growth hormone
promoter activity. J Biol Chem 261: 14733–14736, 1986.
LAVIN TN, BAXTER JD, AND HORITA S. The thyroid hormone receptor
binds to multiple domains of the rat growth hormone 5⬘-flanking
sequence. J Biol Chem 263: 9418 –9426, 1988.
LAZAR MA. Sodium butyrate selectively alters thyroid hormone
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
247.
THYROID HORMONE ACTION
1134
284.
285.
286.
287.
288.
289.
291.
292.
293.
294.
295.
296.
297.
298.
299.
300.
301.
302.
303.
receptor gene expression in GH3 cells. J Biol Chem 265: 17474 –
17477, 1990.
LAZAR MA. Thyroid hormone receptors: multiple forms, multiple
possibilities. Endocr Rev 14: 348 –399, 1993.
LAZAR MA. Nuclear hormone receptors: from molecules to diseases.
J Invest Med 47: 364 –368, 1999.
LAZAR MA. Transcriptional repression by thyroid hormone receptor
(Abstract). Proc Int Symp Mol Thyroidol 7th Hamamatsu Japan
2000, p. 10.
LAZAR MA AND BERRODIN TJ. Thyroid hormone receptors form distinct nuclear protein-dependent and independent complexes with a
thyroid hormone response element. Mol Endocrinol 4: 1627–1635,
1990.
LAZAR MA, BERRODIN TJ, AND HARDING HH. Differential DNA binding
by monomeric, homodimeric, and potentially heteromeric forms of
the thyroid hormone receptor. Mol Cell Biol 11: 5005–5015, 1991.
LAZAR MA AND CHIN WW. Nuclear thyroid hormone receptors. J Clin
Invest 86: 1777–1782, 1990.
LAZAR MA, HODIN RA, CARDONA GR, AND CHIN WW. Gene expression
from the c-erbAa/Rev-erbAa genomic locus: potential regulation of
alternative splicing by complementary transcripts from opposite
DNA strands. J Biol Chem 265: 12859 –12863, 1990.
LAZAR MA, HODIN RA, AND CHIN WW. Human carboxyl-terminal
variant of a-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone. Proc Natl Acad
Sci USA 86: 7771–7774, 1989.
LAZAR MA, HODIN RA, DARLING DS, AND CHIN WW. Identification of a
rat c-erbAa-related protein which binds deoxyribonucleic acid and
does not bind thyroid hormone. Mol Endocrinol 2: 893–901, 1989.
LAZAR MA, HODIN RA, DARLING DS, AND CHIN WW. A novel member
of the thyroid/steroid hormone receptor family is encoded by the
opposite strand of the rat c-erbAa transcriptional unit. Mol Cell Biol
9: 1128 –1136, 1989.
LEE IJ, DRIGGERS PH, MEDIN JA, NIKODEM VM, AND OZATO K. Recombinant thyroid hormone receptor and retinoid X receptor stimulate
ligand-dependent transcription in vitro. Proc Natl Acad Sci USA 91:
1647–1651, 1994.
LEE JW, CHOI HS, GYURIS J, BRENT R, AND MOORE DD. Two classes of
proteins dependent on either the presence or absence of thyroid
hormone for interaction with the thyroid hormone receptor. Mol
Endocrinol 9: 243–254, 1995.
LEE JW, RYAN F, SWAFFIELD JC, JOHNSTON SA, AND MOORE DD. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature 374: 91–94, 1995.
LEE LR, MORTENSEN RM, LARSON CA, AND BRENT GA. Thyroid hormone receptor-alpha inhibits retinoic acid-responsive gene expression and modulates retinoic acid-stimulated neural differentiation
in mouse embryonic stem cells. Mol Endocrinol 8: 746 –756, 1994.
LEE SK, ANZICK SL, CHOI JE, BUBENDORF L, GUAN XY, JUNG YK,
KALLIONIEMI OP, KONONEN J, TRENT JM, AZORSA D, JHUN BH, CHEONG
JH, LEE YC, MELTZER PS, AND LEE JW. A nuclear factor, ASC-2, as a
cancer-amplified transcriptional coactivator essential for liganddependent transactivation by nuclear receptors in vivo. J Biol
Chem 274: 34283–34293, 1999.
LEEDMAN PJ, STEIN AR, AND CHIN WW. Regulated specific protein
binding to a conserved region of the 3⬘-untranslated region of
thyrotropin beta-subunit mRNA. Mol Endocrinol 9: 375–387, 1995.
LEID M, KASTNER P, LYONS R, NAKSATRI H, SAUNDERS M, ZACHAREWSKI
T, CHEM JY, STAUB M, GARNIER A, MADER S, AND CHAMBON P. Purification, cloning and RXR identity of the HeLa cell factor with which
RAR or TR heterodimerizes to bind target sequences efficiently.
Cell 68: 377–395, 1992.
LEITMAN DC, COSTA CHRM, GRAF H, BAXTER JD, AND RIBEIRO RCJ.
Thyroid hormone activation of transcription is potentiated by activators of cAMP-dependent protein kinase. J Biol Chem 271:
21950 –21955, 1996.
LEONHARDT U, GERDES E, RITZEL U, SCHAFER G, BECKER W, AND
RAMADORI G. Immunoreactive leptin and leptin mRNA expression
are increased in rat hypo- but not hyperthyroidism. J Endocrinol
163: 115–121, 1999.
LEVACHER C, SZTALRYD C, KINEBANYAN MF, AND PICON L. Effects of
thyroid hormones on adipose tissue development in Sherman and
Zucker rats. Am J Physiol Cell Physiol 246: C50 –C56, 1984.
Volume 81
304. LEVIN AA, STURZENBECKER LJ, KAXMER S, BOSAKOWSKI T, HUSELTON C,
ALLENBY G, SPECK L, KRATZEISEN C, ROSENBERGER M, LOVEY A, AND
GRIPPO JF. 9-Cis retinoic acid stereoisomer binds and activates the
nuclear receptor RXRa. Nature 355: 359 –361, 1992.
305. LEZOUALC’H F, HASSAN AH, GIRAUD P, LOEFFLER JP, LEE SL, AND
DEMENEIX BA. Assignment of the beta-thyroid hormone receptor to
3,5,3⬘-triiodothyronine-dependent inhibition of transcription from
thyrotropin-releasing hormone promoter in chick hypothalamic
neurons. Mol Endocrinol 6: 1797–1804, 1992.
306. LI H, GOMES PJ, AND CHEN JD. RAC3, a steroid/nuclear receptorassociated coactivator that is related to SRC-1 and TIF2. Proc Natl
Acad Sci USA 94: 8479 – 8484, 1997.
307. LIN Y, THACORE HR, DAVIS PJ, AND DAVIS FB. Thyroid hormone
potentiates the antiviral action of interferon-gamma in cultured
human cells. J Clin Endocrinol Metab 79: 62– 65, 1994.
308. LIN KH, ASHIZAWA K, AND CHENG SY. Phosphorylation stimulates the
transcriptional activity of the human beta 1 thyroid hormone receptor. Proc Natl Acad Sci USA 89: 7737–7741, 1992.
309. LIN ZHU Y, SHIEH C, HSU T, CHEN G, MCPHIE P, AND CHENG SY.
Identification of naturally occurring dominant negative mutants of
thyroid hormone a1 and b1 receptors in a human hepatocellular
carcinoma cell lines. Endocrinology 137: 4073– 4081, 1996.
310. LIN S AND GREEN MR. Mechanism of action of an acidic transcriptional activator in vitro. Cell 64: 971–981, 1991.
311. LIU Y, TAKESHITA A, MISITI S, CHIN WW, AND YEN PM. Lack of
coactivator interaction can be a mechanism for dominant negative
activity by mutant thyroid hormone receptors. Endocrinology 139:
4197– 4204, 1998.
312. LOPEZ G, SCHAUFELE F, WEBB P, HOLLOWAY JM, BAXTER JD, AND
KUSHNER PJ. Positive and negative modulation of jun action by
thyroid hormone receptor at a unique AP1 site. Mol Cell Biol 13:
3042–3049, 1993.
313. LOWELL BB, SUSULIC VS, HAMANN A, LAWITTS JA, HIMMS-HAGEN J,
BOYER BB, KOZAK LP, AND FLIER JS. Development of obesity in
transgenic mice after genetic ablation of brown adipose tissue.
Nature 366: 740 –742, 1993.
314. LUCAS PC, FORMAN BM, SAMUELS HH, AND GRANNER DK. Specificity of
a retinoic acid response element in the phosphoenolpyruvate carboxykinase gene promoter: consequences of both retinoic acid and
thyroid hormone receptor binding. Mol Cell Biol 11: 5164 –5170,
1991.
315. LUISI BF, SCHWABE JW, AND FREEDMAN LP. The steroid/nuclear receptors: from three-dimensional structure to complex function.
Vitam Horm 49: 1– 47, 1994.
316. MA H, HONG H, HUANG SM, IRVINE RA, WEBB P, KUSHNER PJ, COETZEE
GA, AND STALLCUP MR. Multiple signal input and output domains of
the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell
Biol 19: 6164 – 6173, 1999.
316a.MACCHIA PE, TAKEUCHI Y, KAWAI T, CUA K, GAUTHIER K, CHASSANDE O,
SEO H, HAYASHI Y, SAMARUT J, MURATA Y, WEISS RE, AND REFETOFF S.
Increased sensitivity to thyroid hormone in mice with complete
deficiency of thyroid hormone receptor alpha. Proc Natl Acad Sci
USA 98: 349 –354, 2001.
317. MADER S, KUMAR V, VERNEUIL DH, AND CHAMBON P. Three amino
acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element. Nature 338: 271–274, 1989.
318. MADISON LD, AHLQUIST JA, ROGERS SD, AND JAMESON JL. Negative
regulation of the glycoprotein hormone alpha gene promoter by
thyroid hormone: mutagenesis of a proximal receptor binding site
preserves transcriptional repression. Mol Cell Endocrinol 94: 129 –
136, 1993.
319. MANTZOROS CS, ROSEN HN, GREENSPAN SL, FLIER JS, AND MOSES AC.
Short-term hyperthyroidism has no effect on leptin levels in man.
J Clin Endocrinol Metab 82: 497– 499, 1997.
320. MARGOTAT A, LENOIR C, SARKISSIAN G, MALEZET-DESMOULIN C, BALDET
L, JAFFIOL C, AND TORRESANI J. Hypersensitivity to thyroid hormone
action. Proc Int Workshop Thyroid Hormone Resistance 1d Padua
Italy 1995.
321. MARKS M, HALLENBECK PL, NAGATA T, SEGARS JH, APEPELLA E, NIKODEM VM, AND OZATO K. H-2RIIBP (RXRb) heterodimerization
provides a mechanism for combinatorial diversity in the regulation
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
290.
PAUL M. YEN
July 2001
322.
323.
324.
325.
327.
328.
329.
330.
331.
332.
333.
334.
335.
336.
337.
338.
339.
340.
341.
of retinoic acid and thyroid hormone responsive genes. EMBO J 11:
1419 –1435, 1992.
MARTIAL JA, SEEBURG PH, GUENZI D, GOODMAN HM, AND BAXTER JD.
Regulation of growth hormone gene expression: synergistic effects
of thyroid and glucocorticoid hormones. Proc Natl Acad Sci USA
74: 4293– 4295, 1977.
MARTINEZ DE ARRIETA C, MORTE B, COLOMA A, AND BERNAL J. The
human RC3 gene homolog, NRGN contains a thyroid hormoneresponsive element located in the first intron. Endocrinology 140:
335–343, 1999.
MAWAZ Z, TSAI MJ, AND O’MALLEY BW. Specific mutations in the
ligand binding domain selectively abolish the silencing function of
human thyroid hormone receptor beta. Proc Natl Acad Sci USA 92:
11691–11695, 1995.
MCINERNEY EM, ROSE DW, FLYNN SE, WESTIN S, MULLEN TM, KRONES
A, INOSTROZA J, TORCHIA J, NOLTE RT, ASSA-MUNT N, MILBURN MV,
GLASS CK, AND ROSENFELD MG. Determinants of coactivator LXXLL
motif specificity in nuclear receptor transcriptional activation.
Genes Dev 12: 3357–3368, 1998.
MCKENNA NJ, LANZ RB, AND O’MALLEY BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321–344,
1999.
MEIER CA, DICKSTEIN BM, ASHIZAWA K, MCCLASKEY JH, MUCHMORE P,
RANSOM SC, MENKE JB, HAO EH, USALA SJ, BERCU BB, CHENG SY, AND
WEINTRAUB BD. Variable transcriptional activity and ligand binding
of mutant b1–3,5,3⬘ triiodothyronine receptors from four families
with generalized resistance to thyroid hormone. Mol Endocrinol 6:
248 –258, 1992.
MEUNIER PJ, BIANCHI GGS, EDOUARD CM, BERNARD JC, COURPRON P,
AND VIGNON GE. Bony manifestations of thyrotoxicosis. Orthoped
Clin N Am 3: 745–774, 1972.
MILNE M, KANG MI, CARDONA G, QUAIL JM, BRAVERMAN LE, CHIN WW,
AND BARAN DT. Expression of multiple thyroid hormone receptor
isoforms in rat femoral and vertebral bone and in bone marrow
osteogenic cultures. J Cell Biochem 74: 684 – 693, 1999.
MITSUHASHI TG, TENNYSON GE, AND NIKODEM VM. Alternative splicing
generates messages encoding rat c-erbA proteins that do not bind
thyroid hormone. Proc Natl Acad Sci USA 85: 5804 –5808, 1988.
MIYAJIMA N, HORIUCHI R, SHIBUYA Y, FUKUSHIGE S, MATSUBARA K,
TOYOSHIMA K, AND YAMAMOTO T. Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from
opposite DNA strands of the same genetic locus. Cell 57: 31–39,
1989.
MIYAMOTO T, KANEKO A, KAKIZAWA T, YAJIMA H, KAMIJO K, SEKINE R,
HIRAMATSU K, NISHII Y, HASHIMOTO T, AND HASHIZUME K. Inhibition of
peroxisome proliferator signaling pathways by thyroid hormone
receptor. Competitive binding to the response element. J Biol
Chem 272: 7752–7758, 1997.
MIYAMOTO T, SUZUKI S, AND DEGROOT LJ. High affinity and specificity
of dimeric binding of thyroid hormone receptors to DNA and their
ligand dependent dissociation. Mol Endocrinol 7: 224 –231, 1993.
MONDEN T, WONDISFORD FE, AND HOLLENBERG AN. Isolation and
characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein. J Biol Chem 272: 29834 –29841, 1997.
MOORADIAN AD, SCHWARTZ HL, MARIASH CN, AND OPPENHEIMER JH.
Transcellular and transnuclear transport of 3,5,3⬘-triiodothyronine
in isolated hepatocytes. Endocrinology 117: 2449 –2456, 1985.
MORKIN E. Regulation of myosin heavy chain genes in the heart.
Circulation 87: 1451–1450, 1993.
MOSEKILDE L, ERIKSEN EF, AND CHARLES P. Effects of thyroid hormones on bone and mineral metabolism. Endocrinol Metab Clin N
Am 19: 35– 63, 1990.
MOUSTAID N AND SUL HS. Regulation of expression of the fatty acid
synthase gene in 3T3–L1 cells by differentiation and triiodothyronine. J Biol Chem 266: 18550 –18554, 1991.
MUNDY GR, SHAPIRO JL, BANDELIN JG, CANALIS EM, AND RAISZ LG.
Direct stimulation of bone resorption by thyroid hormones. J Clin
Invest 58: 529 –534, 1976.
MUNOZ A, ZENKE M, GEHERING U, SAP J, BEUG H, AND VENNSTROM B.
Characterization of the hormone binding domain of the chicken
c-erbA/thyroid hormone receptor protein. EMBO J 17: 155–159,
1988.
MURRAY M AND TOWLE H. Identification of nuclear factors that
1135
enhance binding of the thyroid hormone receptor to a thyroid
hormone response element. Mol Endocrinol 3: 1434 –1442, 1989.
342. NAAR AM, BOUTIN JM, LIPKIN SM, YU VC, HOLLOWAY JM, GLASS CK,
AND ROSENFELD MG. The orientation and spacing of core DNAbinding motifs dictate selective transcriptional responses to three
nuclear receptors. Cell 65: 1255–1266, 1991.
343. NAGAYA T, EBERHARDT NL, AND JAMESON JL. Thyroid hormone resistance syndrome: correlation of dominant negative activity and
location of mutations. J Clin Endocrinol Metab 77: 982–990, 1993.
344. NAGAYA T AND JAMESON JL. Thyroid hormone receptor dimerization
is required for dominant negative inhibition by mutations that
cause thyroid hormone resistance. J Biol Chem 268: 15766 –15771,
1993.
345. NAGAYA T, MADISON LD, AND JAMESON JL. Thyroid hormone receptor
mutants that cause resistance to thyroid hormone: evidence for
receptor competition for DNA sequences in target genes. J Biol
Chem 27: 13014 –13019, 1992.
346. NAGL SB, NELSON CC, ROMANIUK PJ, AND ALLISON LA. Constitutive
transactivation by thyroid hormone receptor and a novel pattern of
activity of its ongenic homolog v-erbA in Xenopus oocytes. Mol
Endocrinol 9: 1522–1532, 1995.
347. NAGY L, KAO HY, CHAKRAVARTI D, LIN RJ, HASSIG CA, AYER DE,
SCHREIBER SL, AND EVANS RM. Nuclear receptor repression mediated
by a complex containing SMRT, mSin3A, and histone deacetylase.
Cell 89: 373–380, 1997.
348. NAGY L, KAO HY, LOVE JD, LI C, BANAYO E, GOOCH JT, KRISHNA V,
CHATTERJEE K, EVANS RM, AND SCHWABE JW. Mechanism of corepressor binding and release from nuclear hormone receptors. Genes
Dev 13: 3209 –3216, 1999.
349. NAKAI AS, SEINO A, SAKURAI A, SZILAK I, BELL GI, AND DEGROOT LJ.
Characterization of a thyroid hormone receptor expressed in human kidney and other tissues. Proc Natl Acad Sci USA 85: 2781–
2785, 1988.
350. NAKAJIMA T, UCHIDA C, ANDERSON SF, LEE CG, HURWITZ J, PARVIN JD,
AND MONTMINY M. RNA helicase A mediates association of CBP with
RNA polymerase II. Cell 90: 1107–1112, 1997.
351. NAN X, NG HH, JOHNSON CA, LAHERTY CD, TURNER BM, EISENMAN RN,
AND BIRD A. Transcriptional repression by the methyl-CpG-binding
protein MeCP2 involves a histone deacetylase complex. Nature
393: 386 –389, 1998.
352. NAWAZ Z, BANIAHMAD C, BURRIS TP, STILLMAN DJ, O’MALLEY BW, AND
TSAI MJ. The yeast SIN3 gene product negatively regulates the
activity of the human progesterone receptor and positively regulates the activities of GAL4 and the HAP1 activator. Mol Gen Genet
245: 724 –733, 1994.
353. NELSON CC, HENDY SC, AND ROMANIUK PJ. Relationship between
P-box amino acid sequence and DNA binding specificity of the
thyroid hormone receptor. The effects of sequences flanking halfsites in thyroid hormone response elements. J Biol Chem 270:
16988 –16994, 1995.
353a.NG L, HURLEY JB, DIERKS B, SRINIVAS M, SALTO C, VENNSTROM B, REH
TA, AND FORREST D. A thyroid hormone receptor that is required for
the development of green cone photoreceptors. Nat Genet 27:
94 –98, 2001.
354. NOMURA T, KHAN MM, KAUL SC, DONG HD, WADHWA R, COLMENARES C,
KOHNO I, AND ISHII S. Ski is a component of the histone deacetylase
complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev 13: 412– 423, 1999.
355. NORDQUIST DT, KOZAK CA, AND ORR HT. cDNA cloning and characterization of three genes uniquely expressed in cerebellum by
Purkinje neurons. J Neurosci 8: 4780 – 4789, 1988.
356. NOVITZKY D. Triiodothyronine replacement, the euthyroid sick syndrome, and organ transplantation. Transplant Proc 23: 2460 –2462,
1991.
357. NOVITSKY D, COOPER DKC, BARTON CI, GREER A, CHAFFIN J, GRIM J,
AND ZUHDI N. Triiodothyronine as an inotropic agent after open
heart surgery. J Thorac Cardiovasc Surg 98: 972–978, 1989.
358. OBERSTE-BERGHAUS C, ZANGER K, HASHIMOTO K, COHEN RN, HOLLENBERG AN, AND WONDISFORD FE. Thyroid hormone-independent interaction between the thyroid hormone receptor beta2 amino terminus and coactivators. J Biol Chem 275: 1787–1792, 2000.
359. OBREGON MJ, CALVO R, HERNANDEZ A, ESCOBAR DEL REY F, AND
MORREALE DE ESCOBAR G. Regulation of uncoupling protein messen-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
326.
THYROID HORMONE ACTION
1136
360.
361.
362.
363.
364.
366.
367.
368.
369.
370.
371.
372.
373.
374.
375.
376.
377.
378.
379.
380.
ger ribonucleic acid and 5⬘-deiodinase activity by thyroid hormones
in fetal brown adipose tissue. Endocrinology 137: 4721– 4729, 1996.
O’DONNELL AL, ROSEN ED, DARLING DS, AND KOENIG R. Thyroid
hormone receptor mutations that interfere with transcriptional
activation also interfere with receptor interaction with a nuclear
protein. Mol Endocrinol 5: 94 –99, 1991.
OGRYZKO VV, KOTANI T, ZHANG X, SCHLITZ RL, HOWARD T, YANG XJ,
HOWARD BH, QIN J, AND NAKATANI Y. Histone-like TAFs within the
PCAF histone acetylase complex. Cell 94: 35– 44, 1998.
OGRYZKO VV, SCHILTZ RL, RUSSANOVA V, HOWARD BH, AND NAKATANI Y.
The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87: 953–959, 1996.
OIKE Y, TAKAKURA N, HATA A, KANAME T, AKIZUKI M, YAMAGUCHI Y,
YASUE H, ARAKI K, YAMAMURA K, AND SUDA T. Mice homozygous for
a truncated form of CREB-binding protein exhibit defects in hematopoiesis and vasculo-angiogenesis. Blood 93: 2771–2779, 1999.
OJAAMA K, KLEMPERER JD, MACGILVRAY SS, KLEIN I, AND SAMAREL A.
Thyroid hormone, hemodynamic regulation of b-myosin heavy
chain promoter in the heart. Endocrinology 137: 802– 808, 1996.
OJAMAA K, SABET A, KENESSEY A, SHENOY R, AND KLEIN I. Regulation
of rat cardiac Kv1.5 gene expression by thyroid hormone is rapid
and chamber specific. Endocrinology 140: 3170 –3176, 1999.
OLSON DP AND KOENIG RJ. 5⬘-Flanking sequences in thyroid hormone response element half-sites determine the requirement of
retinoid X receptor for receptor-mediated gene expression. J Biol
Chem 272: 9907–9914, 1997.
OLSON DP AND KOENIG RJ. Thyroid function in Rubinstein-Taybi
syndrome. J Clin Endocrinol Metab 82: 3264 –3266, 1997.
OLSON DP, SUN B, AND KOENIG RJ. Thyroid hormone response element architecture affects corepressor release from thyroid hormone receptor dimers. J Biol Chem 273: 3375–3380, 1998.
ONATE SA, TSAI SY, TSAI MJ, AND O’MALLEY BW. Sequence and
characterization of a coactivator for the steroid hormone receptor
superfamily. Science 270: 1354 –1357, 1995.
ONIGATA K, YAGI H, SAKURAI A, NAGASHIMA T, NOMURA Y, NAGASHIMA K,
HASHZUME K, AND MORIKAWA A. A novel point mutation (R243Q) in
exon 7 of the c-erbA beta thyroid hormone receptor gene in a family
with resistance to thyroid hormone. Thyroid 5: 355–358, 1995.
ONO S, SCHWARTZ ID, MUELLER OT, ROOT AW, USALA SJ, AND BERCU
BB. Homozygosity for a dominant negative thyroid hormone receptor responsible for generalized thyroid hormone resistance. J Clin
Endocrinol Metab 73: 990 –994, 1991.
OPPENHEIMER JH, KOERNER D, SCHWARTZ HL, AND SURKS MI. Specific
nuclear triiodothyronine binding sites in rat liver and kidney. J Clin
Endocrinol Metab 35: 330 –333, 1972.
OPPENHEIMER JH AND SCHWARTZ HL. Molecular basis of thyroid hormone-dependent brain development. Endocr Rev 18: 462– 475,
1997.
OPPENHEIMER JH, SCHWARTZ HL, LANE JT, AND THOMPSON MP. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest 87: 125–132, 1991.
OPPENHEIMER JH, SCHWARTZ HL, MARIASH CN, KINLAW WB, WONG
NCW, AND FREAKE HC. Advances in our understanding of thyroid
hormone action at the cellular level. Endocr Rev 8: 288 –308, 1987.
OPPENHEIMER JH, SCHWARTZ HL, AND STRAIT KA. An integrated view
of thyroid hormone actions in vivo. In: Molecular Endocrinology:
Basic Concepts and Clinical Correlations, edited by Weintraub B.
New York: Raven, 1995, p. 249 –268.
OPPENHEIMER JH, SCHWARTZ HL, AND SURKS MI. Tissue differences in
the concentration of triiodothyronine nuclear binding sites in the
rat: liver, kidney, pituitary, heart, brain, spleen, and testis. Endocrinology 95: 897–903, 1974.
OSTY J, VALENSI P, SAMSON M, FRANCON J, AND BLONDEAU JP. Transport of thyroid hormones by human erythrocytes: kinetic characterization in adults and newborns. J Clin Endocrinol Metab 71:
1589 –1595, 1990.
PACHUCKI J, BURMEISTER LA, AND LARSEN PR. Thyroid hormone regulates hyperpolarization-activated cyclic nucleotide-gated channel
(HCN2) mRNA in the rat heart. Circ Res 85: 498 –503, 1999.
PACKARD CJ, SHEPHERD J, LINDSAY GM, GAW A, AND TASKINEN MR.
Thyroid replacement therapy and its influence on postheparin
plasma lipases and apolipoprotein-B metabolism in hypothyroidism. J Clin Endocrinol Metab 76: 1209 –1216, 1993.
Volume 81
381. PARMA J, DUPREZ L, VAN SANDE J, HERMANS J, ROCMANS P, VAN VLIET
G, COSTAGLIOLA S, RODIEN P, DUMONT JE, AND VASSART G. Diversity
and prevalence of somatic mutations in the thyrotropin receptor
and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin
Endocrinol Metab 82: 2695–2701, 1997.
382. PARMENTIER M, LIBERT F, MAENHAUT C, LEFORT A, GERARD C, PERRET
J, VAN SANDE J, DUMONT JE, AND VASSART G. Molecular cloning of the
thyrotropin receptor. Science 246: 1620 –1622, 1989.
383. PASCHKE R AND LUDGATE M. The thyrotropin receptor in thyroid
diseases. N Engl J Med 337: 1675–1681, 1997.
384. PASCUAL AS, CASANOVA J, AND SAMUELS HH. Photoaffinity labeling of
thyroid hormone receptors in intact cells. J Biol Chem 257: 9640 –
9647, 1982.
385. PASTOR R, BERNAL J, AND RODRIGUEZ-PENA A. Unliganded c-erbA/
thyroid hormone receptor induces trkB expression in neuroblasoma cells. Oncogene 9: 1081–1089, 1994.
386. PAZOS-MOURA C, ABEL ED, BOERS ME, MOURA E, HAMPTON TG, WANG
J, MORGAN JP, AND WONDISFORD FE. Cardiac dysfunction caused by
myocardium-specific expression of a mutant thyroid hormone receptor. Circ Res 86: 700 –706, 2000.
387. PELLEQUER JL, WAGER-SMITH KA, KAY SA, AND GETZOFF ED. Photoactive yellow protein: a structural prototype for the three-dimensional fold of the PAS domain superfamily. Proc Natl Acad Sci USA
95: 5884 –5890, 1998.
388. PEREZ P, SCHONTHAL A, AND ARANDA A. Repression of c-fos gene
expression by thyroid hormone and retinoic acid receptors. J Biol
Chem 268: 23538 –23543, 1993.
389. PEREZ-CASTILLO A, HERNANDEX A, PIPAON C, SANTOS A, AND OBREGON
MJ. Multiple regulation of S14 gene expression during brown fat
differentiation. Endocrinology 133: 545–552, 1993.
390. PERISSI V, STASZEWSKI LM, MCINERNEY EM, KUROKAWA R, KRONES A,
ROSE DW, LAMBERT MH, MILBURN MV, GLASS CK, AND ROSENFELD MG.
Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev 13: 3198 –3208, 1999.
391. PERLMANN T, RANGARAJAN PN, UMESONO K, AND EVANS RM. Determinants for selective RAR and TR recognition of direct repeat HREs.
Genes Dev 7: 1411–1422, 1993.
392. PERLMANN T, UMESONO K, RANGARAJAN PN, FORMAN BM, AND EVANS
RM. Two distinct dimerization interfaces differentially modulate
target gene specificity of nuclear hormone receptors. Mol Endocrinol 10: 958 –966, 1996.
393. PETRIJ F, GILES RH, DAUWERSE HG, SARIS JJ, HENNEKAM RC, MASUNO
M, TOMMERUP N, VAN OMMEN GJ, GOODMAN RH, PETERS DJ, AND
BREUNING MH. Rubinstein-Taybi syndrome caused by mutations in
the transcriptional co-activator CBP. Nature 376: 348 –351, 1995.
394. PETTY KJ. Tissue- and cell-specific distributions of protein interactions that interact with human b-thyroid hormone receptor. Mol
Cell Endocrinol 108: 131–142, 1994.
395. PETTY KJ, DESVERGNE B, MITSUHASHI T, AND NIKODEM VM. Identification of a thyroid hormone response element in the malic enzyme
gene. J Biol Chem 265: 7395–7400, 1990.
396. PETTY KJ, KRIMKEVICH YI, AND THOMAS D. A TATA binding proteinassociated factor functions as a coactivator for thyroid hormone
receptors. Mol Endcrinol 10: 1632–1645, 1996.
397. PFAFF DW, KOW LM, ZHU YS, SCOTT RE, WU-PENG SX, AND DELLOVADE
T. Hypothalamic cellular and molecular mechanisms helping to
satisfy axiomatic requirements for reproduction. J Neuroendocrinol 8: 325–336, 1996.
398. PIEDRAFITA FJ, ORTIZ MA, AND PFAHL M. Thyroid hormone receptorbeta mutants associated with generalized resistance to thyroid
hormone show defects in their ligand-sensitive repression function.
Mol Endocrinol 9: 1533–1548, 1995.
399. PINKNEY JH, GOODRICK SJ, KATZ J, JOHNSON AB, LIGHTMAN SL, COPPACK
SW, AND MOHAMED-ALI V. Leptin and the pituitary-thyroid axis: a
comparative study in lean, obese, hypothyroid and hyperthyroid
subjects. Clin Endocrinol 49: 583–588, 1998.
400. POHLENZ J, MANDERS L, SADOW PM, KANSAL PC, REFETOFF S, AND
WEISS RE. A novel point mutation in cluster 3 of the thyroid
hormone receptor beta gene (P247L) causing mild resistance to
thyroid hormone. Thyroid 9: 1195–1203, 1999.
401. POHLENZ J, WEISS RE, MACCHIA PE, PANNAIN S, LAU IT, HO H, AND
REFETOFF S. Five new families with resistance to thyroid hormone
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
365.
PAUL M. YEN
July 2001
402.
403.
404.
405.
406.
408.
409.
410.
411.
412.
413.
414.
415.
416.
417.
418.
419.
420.
421.
not caused by mutations in the thyroid hormone receptor beta
gene. J Clin Endocrinol Metab 84: 3919 –3928, 1999.
PONTING CP AND ARAVIND L. PAS: a multifunctional domain family
comes to light. Curr Biol 7: R674 –R677, 1997.
POP VJ, KUIJPENS JL, VAN BAAR AL, VERKERK G, VAN SON MM, DE
VIJLDER JJ, VULSMA T, WIERSINGA WM, DREXHAGE HA, AND VADER HL.
Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in
infancy. Clin Endocrinol 50: 149 –155, 1999.
POU MA AND TORRESANI J. Coordinated stimulation of triiodothyronine of fatty acid synthesis and isoproterenol-sensitive fatty acid
release in two preadipocyte cell lines of lean or genetically obese
mice. Horm Metab Res 21: 468 – 472, 1989.
POWER RF, MAIN S, CODINA J, CONEELY OM, AND O’MALLEY BW.
Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 254: 1636 –1639, 1991.
PUIGSERVER P, WU Z, PARK CW, GRAVES R, WRIGHT M, AND SPIEGELMAN
BM. A cold-inducible coactivator of nuclear receptors linked to
adaptive thermogenesis. Cell 92: 829 – 839, 1998.
QI JS, DESAI-YAJNIK V, GREENE ME, RAAKA BM, AND SAMUELS HH. The
ligand-binding domains of the thyroid hormone/retinoic receptor
gene subfamily function in vivo to mediate heterodimerizatin, gene
silencing, and transactivation. Mol Cell Biol 15: 1817–1825, 1995.
RABELO R, SCHIFMAN A, RUBIO A, SHENG X, AND SILVA JE. Delineation
of thyroid hormone-responsive sequences within a critical enhancer in the uncoupling protein gene. Endocrinology 136: 1003–
1013, 1995.
RABIE A, FAVRE C, CLAVEL MC, AND LEGRAND J. Effects of thyroid
dysfunction on the development of the rat cerebellum, with special
reference to cell death within the internal granular layer. Brain Res
120: 521–531, 1977.
RABIE A AND LEGRAND J. Effects of thyroid hormone and undernourishment on the amount of synaptosomal fraction in the cerebellum
of the young rat. Brain Res 61: 267–278, 1973.
RACHEZ C, GAMBLE M, CHANG CP, ATKINS GB, LAZAR MA, AND FREEDMAN LP. The DRIP complex and SRC-1/p160 coactivators share
similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol 20: 2718 –2726, 2000.
RACHEZ C, LEMON BD, SULDAN Z, BROMLEIGH V, GAMBLE M, NAAR AM,
ERDJUMENT-BROMAGE H, TEMPST P, AND FREEDMAN LP. Ligand-dependent transcription activation by nuclear receptors requires the
DRIP complex. Nature 398: 824 – 828, 1999.
RASTINEJAD F, PERLMANN T, EVANS RM, AND SIGLER PB. Structural
determinants of nuclear receptor assembly on DNA direct repeats.
Nature 375: 203–211, 1995.
REFETOFF S, DEWIND LT, AND DEGROOT LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high
PBI: possible target organ refractoriness to thyroid hormone.
J Clin Endocrinol Metab 27: 279 –294, 1967.
REFETOFF S, WEISS RA, AND USALA SJ. The syndromes of resistance
to thyroid hormone. Endocr Rev 14: 348 –399, 1993.
REGINATO MJ, ZHANG J, AND LAZAR MA. DNA-independent and DNAdependent mechanisms regulate the differential heterodimerization of the isoforms of the thyroid hormone receptor with retinoid
X receptor. J Biol Chem 271: 28199 –28205, 1996.
RENAUD JP, ROCHEL N, RUFF M, VIVAT V, CHAMBON P, GRONEMEYER H,
AND MORAS D. Crystal structure of the RAR-gamma ligand-binding
domain bound to all-trans retinoic acid. Nature 378: 681– 689, 1995.
RHODES SJ, CHEN R, DIMATTIA GE, SCULLY KM, KALLA KA, LIN SC, YU
VC, AND ROSENFELD MG. A tissue-specific enhancer confers pit-1
dependent morphogen inducibility and autoregulation on the pit-1
gene. Genes Dev 7: 913–932, 1993.
RIBEIRO RC, APRILETTI JW, WAGNER RL, WEST BL, FENG W, HUBER R,
KUSHNER PJ, NILSSON S, SCANLAN T, FLETTERICK RJ, SCHAUFELE F, AND
BAXTER JD. Mechanisms of thyroid hormone action: insights from
X-ray crystallographic and functional studies. Rec Prog Horm Res
53: 351–394, 1998.
RIBEIRO RC, APRILETTI JW, YEN PM, CHIN WW, AND BAXTER JD.
Heterodimerization and deoxyribonucleic acid-binding properties
of retinoic X receptor-related factor. J Biol Chem 135: 2076 –2085,
1994.
RIBEIRO RCJ, CAVALIERI RR, LOMRI N, RAHAMAOUI CM, BAXTER JD, AND
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
434.
435.
436.
437.
438.
439.
440.
441.
1137
SCHARSCHMIDT BF. Thyroid hormone export regulates cellular hormone content and response. J Biol Chem 271: 17147–17151, 1996.
RIBEIRO RCJ, KUSHMAN PJ, APRILETTI JW, WEST BL, AND BAXTER JD.
Thyroid hormone alters in vitro DNA binding of monomers and
dimers of thyroid hormone receptors. Mol Endocrinol 6: 1142–
1152, 1992.
RIDGWAY ND AND DOLPHIN PJ. Serum activity and hepatic secretion
of lecithin:cholesterol acyltransferase in experimental hypothyroidism and hypercholesterolemia. J Lipid Res 26: 1300 –1313,
1985.
RIVKEES SA, BODE HH, AND CRAWFORD JD. Long-term growth in
juvenile acquired hypothyroidism: the failure to achieve normal
adult stature. N Engl J Med 318: 599 – 602, 1988.
RODRIGUEZ-PENA A. Oligodendrocyte development and thyroid hormone. J Neurobiol 40: 497–512, 1999.
ROGATSKY I, CRONIN MJ, AND YAMAMOTO KR. Transcriptonal regulatory complexes that confer represion by the gllucocorticoid receptor (Abstract). In: Nuclear Receptors 2000, Keystone Symposium.
Steamboat Springs, CO: Keystone, 2000, p. 369.
ROHRER DK AND DILLMANN WH. Thyroid hormone markedly increases the mRNA coding for sarcoplasmic reticulum Ca2⫹-ATPase
in the rat heart. J Biol Chem 263: 6941– 6944, 1988.
ROMANI A, MARFELLA C, AND LAKSHMANAN M. Mobilization of Mg2⫹
from rat heart and liver mitochondria following the interaction of
thyroid hormone with adenine nucleotide translocase. Thyroid 6:
513–519, 1996.
ROSEN ED, O’DONNELL AL, AND KOENIG RJ. Ligand-dependent synergy of thyroid hormone and retinoid X receptors. J Biol Chem 267:
22010 –22013, 1992.
ROSS DS. Hyperthyroidism, thyroid hormone therapy, and bone.
Thyroid 4: 319 –326, 1994.
ROWAN BG, WEIGEL NL, AND O’MALLEY BW. Phosphorylation of
steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem 275: 4475– 4483, 2000.
RUBIO R, RAASMAJA A, AND SILVA JE. Thyroid hormone and norepinephrine signaling in brown adipose tissue: differential effects of
thyroid hormone on beta 3-adrenergic receptors in brown and
white adipose tissue. Endocrinology 136: 3277–3284, 1995.
SAATCIOGLU F, DENG T, AND KARIN M. A novel cis element mediating
ligand-independent activation by c-erbA: implications for hormonal
regulation. Cell 75: 1095–1105, 1993.
SADOVSKY Y, WEBB P, LOPEZ G, BAXTER JD, FITZPATRICK PM, GIZANGGINSBERG E, CAVAILLES V, PARKER MG, AND KUSHNER PJ. Transcriptional activators differ in their responses to overexpression of
TATA-box-binding protein. Mol Cell Biol 15: 1554 –1563, 1995.
SAFER JD, COHEN RN, HOLLENBERG AN, AND WONDISFORD FE. Defective release of corepressor by hinge mutants of the thyroid hormone receptor found in patients with resistance to thyroid hormone. J Biol Chem 273: 30175–30182, 1998.
SAFER JD, O’CONNOR MG, COLAN SD, SRINIVASAN S, TOLLIN SR, AND
WONDISFORD FE. The thyroid hormone receptor-beta gene mutation
R383H is associated with isolated central resistance to thyroid
hormone. J Clin Endocrinol Metab 84: 3099 –3109, 1999.
SAKURAI A, MIYAMOTO T, REFETOFF S, AND DEGROOT LJ. Dominant
negative transcriptional regulation by a mutant thyroid hormone
receptor b in a family with generalized resistance to thyroid hormone. Mol Endocrinol 4: 1988 –1994, 1990.
SAKURAI A, TAKEDA K, AIN K, CECCARELLI P, NAKAI A, SEINO S, BELL GI,
REFETOFF S, AND DEGROOT LJ. Generalized resistance to thyroid
hormone associated with a mutation in the ligand-binding domain
of the human thyroid hormone receptor b. Proc Natl Acad Sci USA
86: 8977– 8981, 1989.
SAMSON M, OSTY J, AND BLONDEAU JP. Identification by photoaffinity
labeling of a membrane thyroid hormone-binding protein associated with the triiodothyronine transport system in rat erythrocytes.
Endocrinology 132: 2470 –2476, 1993.
SAMUELS HH, FORMAN BM, HOROWITZ ZD, AND YE S. Regulation of
gene expression by thyroid hormone. J Clin Invest 81: 957–967,
1988.
SAMUELS HH AND TSAI JS. Thyroid hormone action in cell culture:
demonstration of nuclear receptors in intact cells and isolated
nuclei. Proc Natl Acad Sci USA 70: 3488 –3492, 1973.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
407.
THYROID HORMONE ACTION
1138
PAUL M. YEN
“finger” structures in the glucocorticoid receptor defined by sitedirected mutagenesis. EMBO J 7: 2503–2508, 1988.
461. SEVERSON DL AND FLETCHER T. Effect of thyroid hormones on acid
cholesterol ester hydrolase activity in rat liver, heart and epididymal fat pads. Biochim Biophys Acta 675: 256 –264, 1981.
461a.SHANG Y, HU X, DIRENZO J, LAZAR MA, AND BROWN M. Cofactor
dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103: 843– 852, 2000.
461b.SHARMA D AND FONDELL JD. Temporal formation of distinct thyroid
hormone coactivator complexes in HeLa cells. Mol Endocrinol 14:
2001–2009, 2000.
462. SHERMAN SI, GOPAL J, HAUGEN BR, CHIU AC, WHALEY K, NOWLAKHA P,
AND DUVIC M. Central hypothyroidism associated with retinoid X
receptor-selective ligands. N Engl J Med 340: 1075–1079, 1999.
463. SHI YB, WONG J, PUZIANOWSKI-KUZNICKA M, AND STOLOW MA. Tadpole
competence and tissue-specific temporal regulation of amphibian
metamorphosis: roles of thyroid hormone and its receptors. Bioessays 18: 391–399, 1996.
464. SHUPNIK MA, CHIN WW, AND RIDGWAY EC. T3 regulation of TSH gene
expression. Endocr Res 15: 579 –599, 1989.
465. SHUPNIK MA, GREENSPAN SL, AND RIDGWAY EC. Transcriptional regulation of thyrotropin subunit genes by thyrotropin-releasing hormone and dopamine in pituitary cell culture. J Biol Chem 261:
12675–12679, 1986.
466. SHUPNIK MA AND RIDGWAY EC. Thyroid hormone control of thyrotropin gene expression in rat anterior pituitary cells. Endocrinology 121: 619 – 624, 1987.
467. SHUPNIK MA, RIDGWAY EC, AND CHIN WW. Molecular biology of
thyrotropin. Endocr Rev 10: 459 – 475, 1989.
468. SIEGRIST-KAISER CA, JUGE-AUBRY C, TRANTER MP, EKENBARGER DM,
AND LEONARD JL. Thyroxine-dependent modulation of actin polymerization in cultured astrocytes: a novel extranuclear action of
thyroid hormone. J Biol Chem 265: 5296 –5302, 1990.
469. SILVA JE AND LARSEN PR. Adrenergic activation of triiodothyronine
production in brown adipose tissue. Nature 305: 712–713, 1983.
470. SILVA JE AND LARSEN PR. Potential of brown adiopse tissue type II
thyroxine 5⬘ deiodinase as a local and systemic source of triiodothyronine in rats. J Clin Invest 76: 2296 –2305, 1985.
471. SIMONIDES WS, BRENT GA, THELEN MH, VAN DER LINDEN CG, LARSEN
PR, AND VAN HARDEVELD C. Characterization of the promoter of the
rat sarcoplasmic endoplasmic reticulum Ca2⫹-ATPase 1 gene and
analysis of thyroid hormone responsiveness. J Biol Chem 271:
32048 –32056, 1996.
472. SJOBERG M AND VENNSTROM B. Ligand-dependent and -independent
transactivation by thyroid hormone receptor beta 2 is determined
by the structure of the hormone response element. Mol Cell Biol 15:
4718 – 4726, 1995.
473. SJOBERG M, VENNSTROM B, AND FORREST D. Thyroid hormone receptors in chick retinal development: differential expression of
mRNAs for alpha and N-terminal variant beta receptors. Development 114: 39 – 47, 1992.
475. SMANIK PA, LIU Q, FURMINGER TL, RYU K, XING S, MAZZAFERRI EL, AND
JHIANG SM. Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 226: 339 –345, 1996.
476. SMITH CL, ONATE SA, TSAI MJ, AND O’MALLEY BW. CREB binding
protein acts synergistically with steroid receptor coactivator-1 to
enhance steroid receptor-dependent transcription. Proc Natl Acad
Sci USA 93: 8884 – 8888, 1996.
477. SPANJAARD RA, NGUYEN VP, AND CHIN WW. Rat Rev-erbA alpha, an
orphan receptor related to thyroid hormone receptor, binds to
specific thyroid hormone response elements. Mol Endocrinol 8:
286 –295, 1994.
478. SPANJAARD RA, NGUYEN VP, AND CHIN WW. Repression of glucocorticoid receptor-mediated transcriptional activation by unliganded
thyroid hormone receptor (TR) is TR isoform-specific. Endocrinology 136: 5084 –5092, 1995.
479. SPENCER TE, JENSTER G, BURCIN MM, ALLIS CD, ZHOU J, MIZZEN CA,
MCKENNA NJ, ONATE SA, TSAI SY, TSAI MJ, AND O’MALLEY BW. Steroid
receptor coactivator-1 is a histone acetyltransferase. Nature 389:
194 –1988, 1997.
480. SREENAN S, CARO JF, AND REFETOFF S. Thyroid dysfunction is not
associated with alterations in serum leptin levels. Thyroid 7: 407–
409, 1997.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
442. SANDE S AND PRIVALSKY ML. Identification of TRACs, a family of
cofactors that associate with, and modulate the activity of, nuclear
hormone receptors. Mol Endocrinol 10: 813– 825, 1996.
443. SANDHOFER C, SCHWARTZ HL, MARIASH CN, FORREST D, AND OPPENHEIMER JH. Beta receptor isoforms are not essential for thyroid hormone-dependent acceleration of PCP-2 and myelin basic protein
gene expression in the developing brains of neonatal mice. Mol Cell
Endocrinol 137: 109 –115, 1998.
444. SAP J, MUNOZ A, DAMM K, GOLDBERG Y, GHYSDAEL J, LEUTZ A, BEUG H,
AND VENNSTROM B. The c-erbA protein is a high affinity receptor for
thyroid hormone. Nature 324: 635– 640, 1986.
445. SASAKI S, LESOON-WOOD LA, DEY A, KUWATA T, WEINTRAUB BD, HUMPHREY G, YANG WM, SETO E, YEN PM, HOWARD BH, AND OZATO K.
Ligand-induced recruitment of a histone deacetylase in the negative-feedback regulation of the thyrotropin beta gene. EMBO J 18:
5389 –5398, 1999.
446. SATOH T, YAMADA M, IWASAKI T, AND MORI M. Negative regulation of
the gene for the preprothyrotropin-releasing hormone from the
mouse by thyroid hormone requires additional factors in conjunction with thyroid hormone receptors. J Biol Chem 271: 27919 –
27926, 1996.
447. SCARABOTTOLO L, TREZZI E, ROMA P, AND CATAPANO AL. Experimental
hypothyroidism modulates the expression of the low density lipoprotein receptor by the liver. Atherosclerosis 59: 329 –333, 1986.
448. SCHRADER M, MULLER KM, NAYERI P, KAHLEN S, AND CARLBERG C.
Vitamin D3-thyroid hormone receptor heterodimer polarity directs
ligand sensitivity of transactivation. Nature 370: 382–386, 1994.
449. SCHUELER PA, SCHWARTZ HL, STRAIT KA, MARIASH CN, AND OPPENHEIMER JH. Binding of 3,5,3⬘-triiodothyronine (T3) and its analogs to
the in vitro translation products of c-erbA protooncogenes: differences in the affinity of the a and b forms of the acetic acid analog
and failure of the human testis and kidney products to bind T3. Mol
Endocrinol 4: 227–234, 1990.
450. SCHULE R AND EVANS RM. Cross-coupling of signal transduction
pathways: zinc finger meets leucine zipper. Trends Genet 7: 377–
381, 1991.
451. SCHULE R, RANGARAJAN P, KLIEWER S, RANSONE LJ, BOLADO J, YANG N,
VERMA IM, AND EVANS RM. Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell 62: 1217–1226,
1990.
452. SEELIG SA, LIAW C, TOWLE HC, AND OPPENHEIMER JH. Thyroid hormone attenuates and augments hepatic gene expression at a pretranslational level. Proc Natl Acad Sci USA 78: 4733– 4737, 1981.
453. SEGAL J AND GORDON A. The effects of actinomycin D, puromycin,
cycloheximide, and hydroxyurea on 3⬘5⬘3-triiodo-L-thyronine stimulated 2-deoxy-D-glucose uptake in chick embryo heart cells in
vitro. Endocrinology 101: 150 –156, 1977.
454. SEGAL J AND INGBAR SH. Studies on the mechanism by which
3,5,3⬘triiodothyronine stimulates 2-deoxyglucose uptake in rat thymocytes in vitro. Role of calcium and adenosine 3⬘,5⬘-monophosphate. J Clin Invest 68: 103–110, 1981.
455. SEGAL J AND INGBAR SH. 3,5,3⬘-Triiodothyronine increases 3⬘,5⬘monophosphate concentration and sugar uptake in rat thymocytes
by stimulating adenylate cyclase activity: studies with the adenylate cyclase inhibitor MDL 12330A. Endocrinology 124: 2166 –2171,
1989.
456. SEGARS JH, MARKS MS, HIRSCHFELD S, DRIGGERS PH, MARTINEZ E,
GRIPPO JF, BROWN M, WAHLI W, AND OZATO K. Inhibition of estrogenresponsive gene activation by the retinoid X receptor beta: evidence for multiple inhibitory pathways. Mol Cell Biol 13: 2258 –
2268, 1993.
457. SENSEL MG, LEGRAND-LORANS A, WANG ME, AND BENSADOUN A. Isolation and characterization of clones for the rat hepatic lipase gene
upstream regulatory region. Biochim Biophys Acta 1048: 297–302,
1990.
458. SEO H, VASSART G, BROCAS H, AND REFETOFF S. Triiodothyronine
stimulates specifically growth hormone mRNA in rat pituitary tumor cells. Proc Natl Acad Sci USA 74: 2054 –2058, 1977.
459. SEOL W, CHOI HS, AND MOORE DD. Isolation of proteins that interact
specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72– 85, 1995.
460. SEVERNE Y, WIELAND S, SCHAFFNER W, AND RUSCONI S. Metal binding
Volume 81
July 2001
THYROID HORMONE ACTION
500.
501.
502.
503.
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
514.
515.
516.
517.
518.
519.
inant negative activity of mutant receptors that cause resistance to
thyroid hormone. Endocrinology 139: 640 – 650, 1998.
TAGAMI T, MADISON LD, NAGAYA T, AND JAMESON JL. Nuclear receptor
corepressors activate rather than suppress basal transcription of
genes that are negatively regulated by thyroid hormone. Mol Cell
Biol 17: 2642–2648, 1997.
TAGAMI T, PARK Y, AND JAMESON JL. Mechanisms that mediate negative regulation of the thyroid-stimulating hormone alpha gene by
the thyroid hormone receptor. J Biol Chem 274: 22345–22353, 1999.
TAKEDA K, SAKURAI A, DEGROOT LJ, AND REFETOFF S. Recessive
inheritance of thyroid hormone resistance caused by complete
deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 74: 49 –55, 1992.
TAKESHITA A, CARDONA GR, KOIBUCHI N, SUEN CS, AND CHIN WW.
TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J Biol Chem 272: 27629 –27634, 1997.
TAKESHITA A, OZAWA Y, AND CHIN WW. Nuclear receptor coactivators
facilitate vitamin D receptor homodimer action on direct repeat
hormone response elements. Endocrinology 141: 1281–1284, 2000.
TAKESHITA A, YEN PM, IKEDA M, CARDONA GR, LIU Y, KOIBUCHI N,
NORWITZ ER, AND CHIN WW. Thyroid hormone response elements
differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor
coactivator-1. J Biol Chem 273: 21554 –21562, 1998.
TAKESHITA A, YEN PM, LIU Y, AND CHIN WW. Functional and in vitro
studies of wild-type thyroid hormone receptor and AF-2 mutants
display selective effects on basal repression and transcriptional
activation. Proc Int Congr Endocrinol San Francisco CA 1996, p.
OR1–5.
TAKESHITA A, YEN PM, MISITI S, CARDONA GR, LIU Y, AND CHIN WW.
Molecular cloning and properties of a full-length putative thyroid
hormone receptor coactivator. Endocrinology 137: 3594 –3597,
1996.
TAN KC, SHIU SW, AND KUNG AW. Effect of thyroid dysfunction on
high-density lipoprotein subfraction metabolism: roles of hepatic
lipase and cholesteryl ester transfer protein. J Clin Endocrinol
Metab 83: 2921–2924, 1998.
TATA JR, ERNSTER L, LINDBERG O, ARRHENIUS ESP, AND HEDMAN R.
The action of thyroid hormones at the cell level. Biochem J 86:
408 – 428, 1963.
TATA JR AND WIDNELL CC. Ribonucleic acid synthesis during the
early action of thyroid hormones. Biochem J 98: 604 – 629, 1966.
TAUROG A. Hormone synthesis. In: Werner and Ingbar’s The Thyroid, edited by Braverman L and Utiger R. Philadelphia, PA: Lippincott-Raven, 1996, p. 47– 81.
TAYLOR AH, STEPHAN ZF, STEELE RE, AND WONG NC. Beneficial
effects of a novel thyromimetic on lipoprotein metabolism. Mol
Pharmacol 52: 542–547, 1997.
TAYLOR AH, WISHART P, LAWLESS DE, RAYMOND J, AND WONG NC.
Identification of functional positive and negative thyroid hormoneresponsive elements in the rat apolipoprotein AI promoter. Biochemistry 35: 8281– 8288, 1996.
TEBOUL M, BISMUTH J, GHIRINGEHELLI O, BONNE J, AND TORRESANI J.
Developmental and thyroid regulation of the nuclear T3 receptors/
c-erbA oncogene products in the Ob 17 preadipocyte cell line. J
Receptor Res 11: 865– 882, 1991.
THOMPSON CC. Thyroid hormone-responsive genes in developing
cerebellum include a novel synaptotagmin and a hairless homolog.
J Neurosci 16: 7832–7840, 1996.
THOMPSON CC AND EVANS RM. Trans-activation by thyroid hormone
receptors: functional parallels with steroid hormone receptor competition for DNA sequences in target genes. Proc Natl Acad Sci
USA 86: 3494 –3498, 1989.
TING YT, BHAT MK, WONG R, AND CHENG S. Tissue-specific stabilization of the thyroid hormone beta1 nuclear receptor by phosphorylation. J Biol Chem 272: 4129 – 4134, 1997.
TING YT AND CHENG SY. Hormone-activated phosphorylation of
human beta1 thyroid hormone nuclear receptor. Thyroid 7: 463–
469, 1997.
TINI M, TSUI LC, AND GIGUERE V. Heterodimeric interaction of the
retinoic acid and thyroid hormone receptors in transcriptional
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
481. STEINSAPIR J, BIANCO AC, BUETTNER C, HARNEY J, AND LARSEN PR.
Substrate-induced down-regulation of human type 2 deiodinase
(hD2) is mediated through proteasomal degradation and requires
interaction with the enzyme’s active center. Endocrinology 141:
1127–1135, 2000.
482. STENOIEN DL, MANCINI MG, PATEL K, ALLEGRETTO EA, SMITH CL, AND
MANCINI MA. Subnuclear trafficking of estrogen receptor-alpha and
steroid receptor coactivator-1. Mol Endocrinol 14: 518 –534, 2000.
483. STERLING K AND BRENNER MA. Thyroid hormone action: effect of
triiodothyronine on mitochondrial adenine nucleotide translocase
in vivo and in vitro. Metabolism 44: 193–199, 1995.
484. STERLING K, BRENNER MA, AND SAKURADA T. Rapid effect of triiodothyronine on the mitochondrial pathway in rat liver in vivo. Science
210: 340 –342, 1980.
485. STERLING K, LAZARUS JH, MILCH PO, SAKURADA T, AND BRENNER MA.
Mitochondrial thyroid hormone receptor: localization and physiological significance. Science 201: 1126 –1129, 1978.
486. STRAIT KA, KINLAW WB, MARIASH CN, AND OPPENHEIMER JH. Kinetics
of induction by thyroid hormone of the two hepatic mRNAs coding
for cytosolic malic enzyme in the hypothyroid and euthyroid states.
Evidence against an obligatory role of S14 protein in malic enzyme
gene expression. J Biol Chem 264: 19784 –19789, 1989.
487. STRAIT KA, SCHWARTZ HL, PEREZ-CASTILLO A, AND OPPENHEIMER JH.
Relationship of c-erbA mRNA content to tissue triiodothyronine
nuclear binding capacity and function in developing and adult rats.
J Biol Chem 265: 10514 –10521, 1990.
488. STRAIT KA, SCHWARTZ HL, SEYBOLD VS, LING NC, AND OPPENHEIMER JH.
Immunofluorescence localization of thyroid hormone receptor protein beta 1 and variant alpha 2 in selected tissues: cerebellar
Purkinje cells as a model for beta 1 receptor-mediated developmental effects of thyroid hormone in brain. Proc Natl Acad Sci USA
88: 3887–3891, 1991.
489. STRAIT KA, ZOU L, AND OPPENHEIMER JH. Beta 1 isoform-specific
regulation of a triiodothyronine-induced gene during cerebellar
development. Mol Endocrinol 6: 1874 –1880, 1992.
490. SUBRAMANIAN A, GULICK A, NEUMAN J, KNOTTS S, AND ROBBINS J.
Transgenic analysis of the thyroid response elements of the acardiac myosin heavy chain gene promoter. J Biol Chem 268:
4331– 4336, 1993.
491. SUEN S AND CHIN WW. Ligand-dependent, Pit-1/GH-1-independent,
transcriptional stimulation of rat growth hormone gene expression
by thyroid hormone receptors in vitro. Mol Cell Biol 13: 1719 –1727,
1993.
492. SUGAWARA A, YEN PM, APRILETTI JW, RIBEIRO RCJ, SACKS DB, BAXTER
JD, AND CHIN WW. Phosphorylation selectively increases triiodothyronine (T3)-receptor homodimer binding to DNA. J Biol Chem 269:
433– 437, 1994.
493. SUGAWARA A, YEN PM, AND CHIN WW. 9-Cis retinoic acid regulation
of rat growth hormone gene expression: potential roles of multiple
nuclear hormone receptors. Endocrinology 135: 1956 –1962, 1994.
494. SUGAWARA A, YEN PM, DARLING DS, AND CHIN WW. Characterization
and tissue expression of multiple triiodothyronine (T3) receptorauxiliary proteins (TRAPs) and their relationship to the retinoid X
receptors (RXRs). Endocrinology 133: 965–971, 1993.
495. SUGAWARA A, YEN PM, QI YP, LECHAN RM, AND CHIN WW. Isoformspecific retinoid X receptor (RXR) antibodies detect differential
expression of RXR proteins in the pituitary gland. Endocrinology
136: 1766 –1744, 1995.
496. SWIERCZYNSKI J, MITCHELL DA, REINHOLD DS, SALATI LM, STAPLETON
SR, KLAUTKY SA, STRUVE AE, AND GOODRIDGE AG. Triiodothyronineinduced accumulations of malic enzyme, fatty acid synthase,
acetyl-coenzyme A carboxylase, and their mRNAs are blocked by
protein kinase inhibitors. Transcription is the affected step. J Biol
Chem 266: 17459 –17466, 1991.
497. SYED MA, THOMPSON MP, PACHUCKI J, AND BURMEISTER LA. The effect
of thyroid hormone on size of fat depots accounts for most of the
changes in leptin mRNA and serum levels in the rat. Thyroid 9:
503–512, 1999.
498. TAGAMI T, GU WX, PEAIRS PT, WEST BL, AND JAMESON JL. A novel
natural mutation in the thyroid hormone receptor defines a dual
functional domain that exchanges nuclear receptor corepressors
and coactivators. Mol Endocrinol 12: 1888 –1902, 1998.
499. TAGAMI T AND JAMESON JL. Nuclear corepressors enhance the dom-
1139
1140
520.
521.
522.
523.
524.
526.
527.
528.
529.
530.
531.
532.
533.
534.
535.
536.
537.
538.
539.
regulation of the gamma F-crystallin everted retinoic acid response
element. Mol Endocrinol 8: 1494 –1506, 1994.
TOMURA H, LAZAR J, PHYILLAIER M, AND NIKODEM VM. The N-terminal
region (A/B) of rat thyroid hormone receptors alpha 1, beta 1, but
not beta 2, contains a strong thyroid hormone-dependent transactivation function. Proc Natl Acad Sci USA 92: 5600 –5604, 1995.
TONE Y, COLLINGWOOD TN, ADAMS M, AND CHATTERJEE VK. Functional
analysis of a transactivation domain in the thyroid hormone beta
receptor. J Biol Chem 269: 31157–31161, 1994.
TONG GX, JEYAKUMAR M, TANEN MR, AND BAGCHI MK. Transcriptional
silencing by unliganded thyroid hormone receptor beta requires a
soluble corepressor that interacts with the ligand-binding domain
of the receptor. Mol Cell Biol 16: 1909 –1920, 1996.
TONG GX, TANEN MR, AND BAGCHI MK. Ligand modulates the interaction of thyroid hormone receptor beta with the basal transcription machinery. J Biol Chem 270: 10601–10611, 1995.
TORA L, GRONEMEYER H, TURCOTTE B, GAUB MP, AND CHAMBON P. The
N-terminal region of the chicken progesterone receptor specifies
target gene activation. Nature 333: 185–188, 1988.
TORA L, WHITE J, BROU C, TASSET D, WEBSTER N, SCHEER E, AND
CHAMBON P. The human estrogen receptor has two independent
nonacidic transcriptional activation functions. Cell 59: 477– 487,
1989.
TORCHIA J, ROSE DW, INOSTROZA J, KAMEI Y, WESTIN S, GLASS CK, AND
ROSENFELD MG. The transcriptional co-activator p/CIP binds CBP
and mediates nuclear-receptor function. Nature 387: 677– 684,
1997.
TOTONOZ P, HU E, AND SPIEGELMAN BM. Stimulation of adipogenesis
in fibroblasts by PPAR gamma 2, a lipid activation transcription
factor. Cell 79: 1147–1156, 1994.
TREMBLAY A, TREMBLAY GB, LABRIE F, AND GIGUERE V. Ligand-independent recruitment of SRC-1 to estrogen receptor beta through
phosphorylation of activation function AF-1. Mol Cell 3: 513–519,
1999.
TUCA A, GIRALT M, VILLARROYA F, VINAS O, MAMPEL T, AND IGLESIAS R.
Ontogeny of thyroid hormone receptors and c-erbA expression
during brown adipose tissue development: evidence of fetal acquisition of the mature thyroid status. Endocrinology 132: 1913–1920,
1993.
TZAGARAKIS-FOSTER C AND PRIVALSKY ML. Phosphorylation of thyroid
hormone receptors by protein kinase A regulates DNA recognition
by specific inhibition of receptor monomer binding. J Biol Chem
273: 10926 –10932, 1998.
UMESONO K AND EVANS RM. Determinants of target gene specificity
for steroid/thyroid hormone receptors. Cell 57: 1139 –1146, 1989.
UMESONO K, MURAKAMI K, THOMPSON CC, AND EVANS RM. Direct
repeats as selective response elements for the thyroid hormone,
retinoic acid, and vitamin D3 receptors. Cell 65: 1255–1266, 1991.
UNDERWOOD AH, EMMETT JC, ELLIS D, FLYNN SB, LEESON PD, BENSON
GM, NOVELLI R, PEARCE NJ, AND SHAH VP. A thyromimetic that
decreases plasma cholesterol levels without increasing cardiac
activity. Nature 324: 425– 429, 1986.
UPPALARI R AND TOWLE HC. Genetic dissection of thyroid hormone
receptor beta: identification of mutations that separate hormone
binding and transcriptonal activation. Mol Cell Biol 15: 1499 –1512,
1995.
USALA SJ, BALE AE, GESUNDHEIT N, WEINBERGER C, LASH RW, WONDISFORD FE, MCBRIDE OW, AND WEINTRAUB BD. Tight linkage between the syndrome of generalized thyroid hormone resistance and
the human c-erbA beta gene. Mol Endocrinol 2: 1217–1220, 1988.
USALA SJ, TENNYSON GE, BALE AE, LASH RW, GESUNDHEIT N, WONDISFORD FE, ACCILI D, HAUSER P, AND WEINTRAUB BD. A base mutation of the c-erbAb thyroid hormone receptor in a kindred with
generalized thyroid hormone resistance. Molecular heterogeneity
in two other kindreds. J Clin Invest 85: 93–100, 1990.
VALCAVI R, DIEGUEZ C, ZINI M, MURUAIS C, CASANUEVA F, AND PORTIOLI
I. Influence of hyperthyroidism on growth hormone secretion. Clin
Endocrinol 38: 515–522, 1993.
VIDAL-PUIG AJ, GRUJIC D, ZHANG CY, HAGEN T, BOSS O, IDO Y, SZCZEPANIK A, WADE J, MOOTHA V, CORTRIGHT R, MUOIO DM, AND LOWELL
BB. Energy metabolism in uncoupling protein 3 gene knockout
mice. J Biol Chem. In press.
VIJLDER JJM DE AND VULSMA T. Hereditary metabolic disorders caus-
540.
541.
542.
543.
544.
545.
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
556.
557.
558.
559.
560.
Volume 81
ing hypothyroidism. In: Werner and Ingbar’s The Thyroid (7th ed.),
edited by Braverman L and Utiger R. Phildadelphia, PA: LipincottRaven, 1996, p. 749 –778.
VOEGEL JJ, HEINE MJ, TINI M, VIVAT V, CHAMBON P, AND GRONEMEYER
H. The coactivator TIF2 contains three nuclear receptor-binding
motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J 17: 507–519, 1998.
VOEGEL JJ, HEINE MJS, ZECHEL C, CHAMBON P, AND GRONEMEYER H.
TIF2, a 160 kD transcriptional mediator for the ligand-dependent
activation function AF-2 of nuclear receptors. EMBO J 15: 3667–
3675, 1996.
VULSMA T, GONS MH, AND DE VIJLDER JJ. Maternal-fetal transfer of
thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321: 13–16, 1989.
WADE PA, GEGONNE A, JONES PL, BALLESTAR E, AUBRY F, AND WOLFFE
AP. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23: 62– 66, 1999.
WAGNER RL, APRILETTI JW, MCGRATH ME, WEST BL, BAXTER JD, AND
FLETTERICK RJ. A structural role for hormone in the thyroid hormone receptor. Nature 378: 690 – 697, 1995.
WEINBERGER C, THOMPSON CC, ONG ES, LEBO R, GRUOL DJ, AND EVANS
RM. The c-erbA gene encodes a thyroid hormone receptor. Nature
324: 641– 646, 1986.
WEIS KE, EKENA K, THOMAS JA, LAZENNEC G, AND KATZENELLENBOGEN
BS. Constitutively active human estrogen receptors containing
amino acid substitutions for tyrosine 537 in the receptor protein.
Mol Endocrinol 10: 1388 –1398, 1996.
WEISS RE, FORREST D, POHLENZ J, CUA K, CURRAN T, AND REFETOFF S.
Thyrotropin regulation by thyroid hormone in thyroid hormone
receptor beta-deficient mice. Endocrinology 138: 3624 –3629, 1997.
WEISS RE, HAYASHI Y, NAGAYA T, PETTY KJ, MURATA Y, TUNCA H, SEO
H, AND REFETOFF S. Dominant inheritance of resistance to thyroid
hormone not linked to defects in the thyroid hormone receptor
alpha or beta genes may be due to a defective co-activator. J Clin
Endocrinol Metab 81: 4196 – 4203, 1996.
WEISS RE, TUMCA H, GERSTEIN HC, AND REFETOFF S. A new mutation
in the thyroid hormone receptor (TR) b gene (V458A) in a family
with resistance to thyroid hormone (RTH). Thyroid 6: 311–312,
1996.
WEISS RE, XU J, NING G, POHLENZ J, O’MALLEY BW, AND REFETOFF S.
Mice deficient in the steroid receptor co-activator 1 (SRC-1) are
resistant to thyroid hormone. EMBO J 18: 1900 –1904, 1999.
WERNER SC. A History of the Thyroid. Philadelphia, PA: Lippincott,
1991.
WIKSTROM L, JOHANSSON C, SALTO C, BARLOW C, CAMPOS BARROS A,
BAAS F, FORREST D, THOREN P, AND VENNSTROM B. Abnormal heart
rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 17: 455– 461, 1998.
WILLIAMS G. Tissue specific expression of two novel thyroid hormone receptor (beta) variants (Abstract). Proc Annu Meet Am
Thyroid Assoc 71d Palm Beach FL 1999, p. 232.
WILLIAMS GR, BLAND R, AND SHEPPARD M. Characterization of thyroid
hormone (T3) receptors in three osteosarcoma cell lines of distinct
osteoblast phenotypes: interactions among T3, vitamin D3, and
retinoid signaling. Endocrinology 1335: 2375–2385, 1994.
WILLIAMS GR AND BRENT GA. Thyroid hormone response elements.
In: Molecular Endocrinology: Basic Concepts and Clinical Correlations, edited by Weintraub B. New York: Raven, 1995, p. 217–239.
WILLIAMS GR, FRANKLYN JA, NEUBERGER JM, AND SHEPPARD MC. Thyroid hormone receptor expression in the “sick euthyroid” syndrome. Lancet 2: 1477–1481, 1989.
WILLIAMS GR, HARNEY JW, MOORE DD, LARSEN PR, AND BRENT GA.
Differential capacity of wild type promoter elements for binding
and trans-activation by retinoic acid and thyroid hormone receptors. Mol Endocrinol 6: 1527–1537, 1992.
WILLIAMS LT, LEFKOWITZ RJ, WATANABE AM, HATHAWAY DR, AND BESCH
HR JR. Thyroid hormone regulation of beta-adrenergic receptor
number. J Biol Chem 252: 2787–2789, 1977.
WISEMAN SA, POWELL JT, HUMPHRIES SE, AND PRESS M. The magnitude of the hypercholesterolemia of hypothyroidism is associated
with variation in the low density lipoprotein receptor gene. J Clin
Endocrinol Metab 77: 108 –112, 1993.
WONDISFORD FE, STEINFELDER HJ, NATIONS M, AND RADOVICK S. AP-1
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
525.
PAUL M. YEN
July 2001
561.
562.
563.
564.
566.
567.
568.
569.
570.
571.
572.
573.
574.
575.
576.
577.
578.
antagonizes thyroid hormone receptor action on thyrotropin bsubunit gene. J Biol Chem 268: 2749 –2754, 1993.
WONG J, SHI YB, AND WOLFFE AP. Determinants of chromatin disruption and transcriptional regulation instigated by the thyroid
hormone receptor: hormone-regulated chromatin disruption is not
sufficient for transcriptional activation. EMBO J 16: 3158 –3171,
1997.
WONG J, SHI YB, AND WOLFFE AP. A role for nucleosome assembly in
both silencing and activation of the Xenopus TR beta A gene by the
thyroid hormone receptor. Genes Dev 9: 2696 –2711, 1996.
WONG R, VASILYEV VV, KUTLER DI, TING YT, WILLINGHAM M, CHENG SY,
AND WEINTRAUB BD. A transgenic model of resistance to thyroid
hormone (RTH): correlation of mutant thyroid hormone b1 receptor (TRb1) levels with the phenotype of fat loss and hyperactivity
(Abstract). J Invest Med 43 Suppl 2: 223A, 1995.
WONG R, VASILYEV VV, TING YT, KUTLER DI, WILLINGHAM MC, WEINTRAUB BD, AND CHENG S. Transgenic mice bearing a human mutant
thyroid hormone beta 1 receptor manifest thyroid function anomalies, weight reduction, and hyperactivity. Mol Med 3: 303–314,
1997.
WOOD DF, DOCHERTY K, RAMSDEN DB, SHENNAN KI, AND SHEPPARD MC.
Thyroid status affects the regulation of prolactin mRNA accumulation by tri-iodothyronine and thyrotrophin-releasing hormone in
cultured rat anterior pituitary cells. J Endocrinol 115: 497–503,
1987.
WOOD WM, DOWDING JM, BRIGHT TM, MCDERMOTT MT, HAUGEN BR,
GORDON DF, AND RIDGWAY EC. Thyroid hormone receptor beta2
promoter activity in pituitary cells is regulated by Pit-1. J Biol
Chem 271: 24213–24220, 1996.
WRUTNIAK C, CASSAR-MALEK I, MARCHAL S, RASCLE A, HEUSSER S,
KELLER J, FLECHON J, DAUSCA M, SAMARUT J, AND GHYSDAEL J. A 43 kD
protein related to c-erb A alpha 1 is located in the mitochondrial
matrix of rat liver. J Biol Chem 270: 16347–16354, 1995.
WU Y, YANG YZ, AND KOENIG RJ. Protein-protein interaction domains
and the heterodimerization of thyroid hormone receptor variant
alpha2 with retinoid X receptors. Mol Endocrinol 12: 1542–1550,
1998.
XU J, LIAO L, NING G, YOSHIDA-KOMIYA H, DENG C, AND O’MALLEY BW.
The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/
TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc Natl Acad
Sci USA 23: 23, 2000.
XU J, QIU Y, DEMAYO FJ, TSAI SY, TSAI MJ, AND O’MALLEY BW. Partial
hormone resistance in mice with disruption of the steroid receptor
coactivator-1 (SRC-1) gene. Science 279: 1922–1925, 1998.
YAGI H, POHLENZ J, HAYASHI Y, SAKURAI A, AND REFETOFF S. Resistance
to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function
that cannot be explained by altered in vitro 3,5,3⬘-triiodothyroinine
binding affinity. J Clin Endocrinol Metab 82: 1608 –1614, 1997.
YALCIN Y, CARMAN D, SHAO Y, ISMAIL-BEIGI F, KLEIN I, AND OJAMAA K.
Regulation of Na/K-ATPase gene expression by thyroid hormone
and hyperkalemia in the heart. Thyroid 9: 53–59, 1999.
YAMADA M, ROGERS D, AND WILBER JF. Exogenous triiodothyronine
lowers thyrotropin-releasing hormone concentrations in the specific hypothalamic nucleus (paraventricular) involved in thyrotropin regulation and also in posterior nucleus. Neuroendocrinology 50: 560 –563, 1989.
YANG XJ, OGRYZKO VV, NISHIKAWA J, HOWARD BH, AND NAKATANI Y. A
p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382: 319 –324, 1996.
YANG Z, HONG SH, AND PRIVALSKY ML. Transcriptional anti-repression. Thyroid hormone receptor beta-2 recruits SMRT corepressor
but interferes with subsequent assembly of a functional corepressor complex. J Biol Chem 274: 37131–37138, 1999.
YANG-YEN HF, CHAMBARD JC, SUN YL, SMEAL T, SCHMIDT TJ, DROUIN J,
AND KARIN M. Transcriptional interference between c-jun and the
glucocorticoid receptor: mutual inhibition of DNA binding due to
direct protein-protein interaction. Cell 62: 1205–1215, 1990.
YAO P, KU G, ZHOU N, SCULLY R, AND LIVINGSTON DM. The nuclear
hormone receptor coactivator SRC-1 is a specific target of p300.
Proc Natl Acad Sci USA 93: 10626 –10631, 1996.
YAO TP, OH SP, FUCHS M, ZHOU ND, CH’NG LE, NEWSOME D, BRONSON
579.
580.
581.
582.
583.
584.
585.
586.
587.
588.
589.
590.
591.
592.
593.
594.
595.
596.
1141
RT, LI E, LIVINGSTON DM, AND ECKNER R. Gene dosage-dependent
embryonic development and proliferation defects in mice lacking
the transcriptional integrator p300. Cell 93: 361–372, 1998.
YARWOOD NJ, GURR JA, SHEPPARD MC, AND FRANKLYN JA. Estradiol
modulates thyroid hormone regulation of the human glycoprotein
hormone alpha subunit gene. J Biol Chem 268: 21984 –21989, 1993.
YE ZS, FORMAN BM, ARANDA A, PASCUAL A, PARK HY, CASANOVA J, AND
SAMUELS HH. Rat growth hormone gene expression. Both cellspecific and thyroid hormone response elements are required for
thyroid hormone regulation. J Biol Chem 263: 7821–7829, 1988.
YEN PM, BRUBAKER JH, APRILETTI JW, BAXTER JD, AND CHIN WW.
Roles of T3 and DNA-binding on thyroid hormone receptor complex formation. Endocrinology 134: 1075–1081, 1994.
YEN PM AND CHIN WW. Molecular mechanisms of dominant negative
activity by nuclear hormone receptors. Mol Endocrinol 8: 1450 –
1454, 1994.
YEN PM AND CHIN WW. New advances in understanding the molecular mechanisms of thyroid hormone action. Trends Endocrinol
Metab 5: 65–72, 1994.
YEN PM, DARLING DS, CARTER RL, FORGIONE M, UMEDA PK, AND CHIN
WW. Triiodothyronine (T3) decreases DNA-binding of receptor homodimers but not receptor-auxiliary protein heterodimers. J Biol
Chem 267: 3565–3568, 1992.
YEN PM, DARLING DS, AND CHIN WW. Basal and thyroid hormone
receptor auxiliary protein-enhanced binding of thyroid hormone
receptor isoforms to native thyroid hormone response elements.
Endocrinology 129: 3331–3336, 1991.
YEN PM, IKEDA M, WILCOX EC, BRUBAKER JH, SPANJAARD RA, SUGAWARA A, AND CHIN WW. Half-site arrangement of hybrid glucocorticoid and thyroid hormone response elements specifies thyroid
hormone receptor complex binding to DNA and transcriptional
activity. J Biol Chem 269: 12704 –12709, 1994.
YEN PM, LIU Y, SUGAWARA A, AND CHIN WW. Vitamin D receptors
(VDRs) repress basal transcription and have dominant negative
activity on T3-mediated transcription. J Biol Chem 271: 10910 –
10916, 1996.
YEN PM, SPANJAARD RA, SUGAWARA A, DARLING DS, NGUYEN VP, AND
CHIN WW. Orientation and spacing of half-sites differentially affect
T3-receptor (TR) monomer, homodimer, and heterodimer binding
to thyroid hormone response elements (TREs). Endocr J 1: 461–
466, 1993.
YEN PM, SUGAWARA A, AND CHIN WW. Triiodothyronine (T3) differentially affects T3-receptor/retinoic acid receptor and T3-receptor/
retinoid X receptor heterodimer binding to DNA. J Biol Chem 267:
23248 –23252, 1992.
YEN PM, SUNDAY ME, DARLING DS, AND CHIN WW. Isoform-specific
thyroid hormone receptor antibodies detect multiple thyroid hormone receptors in rat and human pituitaries. Endocrinology 130:
1539 –1546, 1992.
YEN PM, WILCOX EC, AND CHIN WW. Steroid hormone receptors
selectively affect transcriptional activation but not basal repression by thyroid hormone receptors. Endocrinology 136: 440 –
445, 1995.
YEN PM, WILCOX EC, HAYASHI Y, REFETOFF S, AND CHIN WW. Studies
on the repression of basal transcription (silencing) by artificial and
natural thyroid hormone receptor-b mutants. Endocrinology 136:
2845–2851, 1995.
YOH SM, CHATTERJEE VK, AND PRIVALSKY ML. Thyroid hormone resistance manifests as an aberrant interaction between mutant T3
receptors and transcriptional corepressors. Mol Endocrinol 11:
470 – 480, 1997.
YU VC, DELSERT C, ANDERSEN B, HOLLOWAY JH, DEVARY OV, NAESER
AM, KIM-J BOUTIN SY, GLASS CK, AND ROSENFELD MG. RXR beta: a
co-regulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements.
Cell 67: 1251–1266, 1991.
YUAN CX, ITO M, FONDELL JD, FU ZY, AND ROEDER RG. The TRAP220
component of a thyroid hormone receptor-associated protein
(TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci USA 95:
7939 –7944, 1998.
ZAMIR I, DAWSON J, LAVINSKY RM, GLASS CK, ROSENFELD MG, AND
LAZAR MA. Cloning and characterization of a corepressor and po-
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
565.
THYROID HORMONE ACTION
1142
597.
598.
599.
600.
601.
603.
tential component of the nuclear hormone receptor repression
complex. Proc Natl Acad Sci USA 94: 14400 –14405, 1997.
ZAMIR I, HARDING HP, ADKINS GB, HORLEIN A, GLASS CK, ROSENFELD
MG, AND LAZAR MA. A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Mol Cell Biol 16: 5458 –5465, 1996.
ZARAIN-HERZBERG A, MARQUES J, AND SUKOVICH D. Thyroid hormone
receptor modulates the expression of the rabbit cardiac sarco(endo)plasmic reticulum Ca(2⫹)-ATPase gene. J Biol Chem 269:
1460 –1467, 1994.
ZHANG J, HU X, AND LAZAR MA. A novel role for helix 12 of retinoid
X receptor in regulating repression. Mol Cell Biol 19: 6448 – 6457,
1999.
ZHANG W, BROOKS RL, SILVERSIDES DW, WEST BL, LEIDIG F, BAXTER
JD, AND EBERHARDT ML. Negative thyroid hormone control of human growth hormone gene expression is mediated by 3⬘-untranslated/3⬘flanking DNA. J Biol Chem 267: 15056 –15063, 1992.
ZHANG X, JEYAKUMAR M, AND BAGCHI MK. Ligand-dependent crosstalk between steroid and thyroid hormone receptors. Evidence for
common transcriptional coactivator(s). J Biol Chem 271: 14825–
14833, 1996.
ZHANG XK, HOFFMAN V, TRAN B, GRAUPNER G, AND PFAHL M. Retinoid
X receptor is an auxiliary protein for thyroid hormone and retinoic
acid receptors. Nature 355: 441– 446, 1992.
ZHANG XK, WILLS KN, GRAUPNER G, TZUKERMAN M, HERMANN T, AND
PFAHL M. Ligand-binding domain of thyroid hormone receptors
modulates DNA binding and determines their bifunctional roles.
New Biologist 3: 169 –181, 1991.
Volume 81
604. ZHANG K, WILLS KN, HUSMANN M, HERMANN T, AND PFAHL M. Novel
pathway for thyroid hormone receptor action through interaction
with jun and fos oncogene activities. Mol Cell Biol 11: 6016 – 6025,
1991.
605. ZHU XG, HANOVER JA, HAGER GL, AND CHENG SY. Hormone-induced
translocation of thyroid hormone receptors in living cells visualized using a receptor green fluorescent protein chimera. J Biol
Chem 273: 27058 –27063, 1998.
606. ZHU XG, KANESHIGE M, PARLOW AF, CHEN E, HUNZIKER RD, MCDONALD
MP, AND CHENG SY. Expression of the mutant thyroid hormone
receptor PV in the pituitary of transgenic mice leads to weight
reduction. Thyroid 9: 1137–1145, 1999.
607. ZHU XG, MCPHIE P, LIN KH, AND CHENG SY. The differential hormone-dependent transcriptional activation of thyroid hormone receptor isoforms is mediated by interplay of their domains. J Biol
Chem 272: 9048 –9054, 1997.
608. ZHU S, PFAFF DW, DELLAVERDE TL, YEN PM, AND CHIN WW. Interaction of estrogen and thyroid hormone on regulation of proenkephalin gene expression in hypothalamus and striatum of female rats.
Proc Neurosci Meet San Diego CA 1995, p. 180 –186.
609. ZHU S, YEN PM, CHIN WW, AND PFAFF DW. Estrogen and thyroid
hormone interaction in regulation of gene expression. Proc Natl
Acad Sci USA 93: 12587–12392, 1996.
610. ZIMMERMANN-BELSING T, DREYER M, HOLST JJ, AND FELDT-RASMUSSEN U.
The relationship between the serum leptin concentrations of thyrotoxic patients during treatment and their total fat mass is different
from that of normal subjects. Clin Endocrinol 49: 589 –595, 1998.
Downloaded from http://physrev.physiology.org/ by 10.220.33.2 on May 5, 2017
602.
PAUL M. YEN