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Gene Section
Review
USF1 (upstream transcription factor 1)
Adrie JM Verhoeven
Cardiovascular Research School (COEUR), Department of Biochemistry, Erasmus MC, Rotterdam,
Netherlands (AJMV)
Published in Atlas Database: April 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/USF1ID45856ch1q23.html
DOI: 10.4267/2042/44944
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
homologous bHLH-ZIP transcription factor. USF1 and
USF2 homo- and heterodimers are similarly active in
affecting transcription of most target genes. USF2
homodimers may have additional effects.
Identity
Other names: bHLHb11, FCHL, FCHL1,
HYPLIP1, MLTF, MLTF1, UEF
HGNC (Hugo): USF1
Location: 1q23.3
Local order:
From centromere to telomere:
F11R (F11 receptor) (on reverse strand), TSTD1
(thiosulfate sulfurtransferase (rhodanese)-like domain
containing 1) (on reverse strand), USF1 (upstream
transcription factor 1) (on reverse strand), ARHGAP30
(Rho GTPase activating protein 30) (on reverse strand),
PVRL4 (poliovirus receptor-related 4) (on reverse
strand), KLHDC9 (kelch domain containing 9) (on plus
strand), PFDN2 (prefoldin subunit 2) (on reverse
strand).
Note
USF1 is a bHLH-ZIP transcription factor which forms
homo-dimers or heterodimers with USF2, a highly
DNA/RNA
Description
The human USF1 gene on chromosome 1q23 spans
6.73 kb and 11 exons.
Transcription
The mRNA is about 1870 nt. Translation is from a start
codon in exon 2 and ends at a stop codon in exon 11,
and results in a 310 amino acid protein product. In a
splice variant, an alternative donor splice site within
exon 4 is used; translation from this variant mRNA is
from an in-frame start codon in exon 5, and results in a
251 amino acid protein product (Saito et al., 2003).
Human USF1 gene diagram. Exons 1 through 11 are depicted by boxes, the open reading frames of the USF1 protein and the splice
variant are shown by dark and light green colour code, respectively. The approximate positions of two functional SNPs are also indicated.
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USF1 (upstream transcription factor 1)
Verhoeven AJM
Functional domains of the USF1 protein. The A1 domain is important for E-box dependent transactivation, the USR (USF-specific region)
and A2 domains are important for E-box and initiator element (Inr)-dependent transactivation (Roy et al., 1997). Post-translational
modifications that affect USF1 function are indicated. The protein product of the splice variant lacks the first 59 amino acids, dimerizes
with full-length USF1 protein, which results in its inactivation (Saito et al., 2003).
distribution of E-box like elements in the genome.
Whole-genome ChIP analysis in HepG2 cells identified
2518 USF1 binding sites in chromatin context, of
which 41 % were located within 1 kb of a transcription
start site (Rade-Iglesias et al., 2008). USF1 binding
signals strongly correlate with target gene expression
levels, suggesting that USF1 plays an important role in
transcription activation. USF1 physically interacts with
histone modifying enzymes, transcription preinitiation
complex factors, coactivator and corepressor proteins
(Corre and Galibert, 2005; Huang et al., 2007; Corre et
al., 2009; Wong et al., 2009). In addition, USF1
interacts with other transcription factors to achieve
cooperative transcriptional activation of individual
genes (Corre and Galibert, 2005). USF1 also plays a
crucial role in chromatin barrier insulator function, in
which euchromatin regions are protected from
heterochromatin-induced gene silencing (Huang et al.,
2007). USFs recruit histone modifying enzymes to the
insulator element, which modify the adjacent
nucleosomes thereby maintaining chromatin in an open
state and preventing heterochromatin spread. Similarly,
USFs main function at enhancer elements may be to
render the adjacent region accessible for binding of
other, bona fide transcription factors, by the
recruitment of histone modifying enzymes (Huang et
al., 2007).
Tumor suppression: Several lines of evidence support
the hypothesis that USF1 may act as a tumor
suppressor. First, USF1 is involved in the
transcriptional activation of several tumor suppressor
genes (e.g. p53, APC, BRCA2, PTEN, SSeCKS)
(Corre and Galibert, 2005; Pezzolesi et al., 2007; Bu
and Gelman, 2007), and represses expression of human
telomerase reverse transcriptase TERT (McMurray and
McCance, 2003; Chang et al., 2005). Second, USF1 is
involved in cell cycle control (Cogswell et al., 1995)
and overexpression of USF1 slows G2/M transition in
thyrocytes and thyroid carcinoma cells (Jung et al.,
2007). Third, USF1 overexpression leads to a strong
reduction in cell proliferation in Ha-Ras/c-Myc
transformed fibroblasts (Luo and Sawadogo, 1996).
Fourth, USF1 transactivation activity is completely lost
in three out of six transformed breast cell lines (Ismail
et al., 1999). Fifth, USF1 antagonizes some activities of
the oncoprotein c-Myc, possibly by competing for the
same DNA binding sites (Luo and Sawadogo, 1996;
Protein
Description
USF1 belongs to the bHLH-Zip class of transcription
factors. The bHLH-ZIP domains are important for
DNA binding and dimerization. USF homo- and
heterodimers activate transcription of target genes
through binding either at distal E-box elements or at
pyrimidine-rich Inr elements in the core promoter (Roy
et al., 1997). Whole genome ChIP-chip analysis in
human hepatoma HepG2 cells showed that USF1 and
USF2 bind predominantly to CACGTGAC elements
(Rada-Iglesias et al., 2008). In addition, USF2 but not
USF1 binds to pyrimidine rich elements, suggesting
that transactivation through Inr elements is mainly
through USF2. Transactivation activity critically
depends on post-translational modification of USF1.
DNA binding to the E-box element is increased by
phosphorylation of USF1 by the cdk1, p38 stressactivated kinase, protein kinase A and protein kinase C
pathway (Corre and Galibert, 2005), whereas
phosphorylation through the PI3Kinase pathway leads
to loss of DNA binding activity to the ApoAV
promoter (Nowak et al., 2005). Cellular stress stimuli
such as DNA damage, oxidative stress and heavy metal
exposure, induce p38-mediated phosphorylation at T 153
and increased USF1 transactivation activity. Upon
increased and/or prolonged stress exposure, USF1
phosphorylated at T153 becomes acetylated at K199 with
concomitant loss of transactivation activity (Corre et
al., 2009). In fasting-refeeding cycles, insulin increases
the transactivation activity of USF1 via DNA-PK
mediated phosphorylation of residue S262 and
subsequent acetylation at K237 (Wong et al., 2009).
Expression
The USF1 gene is ubiquitously expressed (Sirito et al.,
1994).
Localisation
The USF1 protein is located in the nucleus.
Function
USF1 has been shown to play an important role in
transcriptional regulation of a huge number of
seemingly unrelated genes (Corre and Galibert, 2005;
Rada-Iglesias et al., 2008), consistent with the abundant
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USF1 (upstream transcription factor 1)
Verhoeven AJM
McMurray and McCance, 2003). Definitive proof that
USF1 is a tumor suppressor protein, e.g. showing that
USF1 knockdown increases cell proliferation and
tumor formation, however, is still missing. This proof
may be hard to gain, as USF2 may compensate for
USF1 loss, and USF2 appears to have a broader
antiproliferative function than USF1 (Luo and
Sadawogo, 1996; Sirito et al., 1998; Vallet et al., 1998).
characteristically show elevation of both cholesterol
and triglycerides in the blood, which is due to increased
VLDL and LDL levels. This is often accompanied by
elevated apoB100 and low HDL levels, and a
preponderance of small dense LDL particles
(Naukkarinen et al., 2006). FCHL is genetically
heterogeneous. One of the loci that is linked to FCHL
is 1q21-q23. Pajukanta et al. (2004) showed that the
dyslipidemia observed in FCHL is linked to the USF1
gene. The disease is associated with a common
haplotype of non-coding SNPs within the USF1 gene.
Carriers of the risk allele show lack of insulin-induced
increase of USF1 expression in skeletal muscle and fat
tissue (Naukkarinen et al., 2009). As USF1 is involved
in regulation of numerous genes of glucose and lipid
metabolism (Corre and Galibert, 2005), non-responsive
USF1 expression may lead to increased production and
reduced metabolism of plasma lipids and lipoproteins.
Homology
The USF1 gene is widely conserved with orthologs
identified in Ciona intestinalis and Drosophila
melanogaster.
Mutations
Note
Of the 121 SNPs in the USF1 gene collected in the
dbSNP database, only the rs4126997 T>C
polymorphism causes a non-synchronous mutation
(V15A missense), but data on allele frequency or
functional effects are not available. The two SNPs that
are shown to be functional, rs2073658 A>G in intron 7
(heterozygosity 0.296) and rs3737787 C>T in the 3'UTR (heterozygosity 0.309), are in almost complete
linkage disequilibrium. The minor allele is
accompanied by normal USF1 expression in human
muscle and fat tissue but loss of insulin-induced
upregulation of USF1 mRNA and known USF1 target
genes (Naukkarinen et al., 2005; Naukkarinen et al.,
2009), as well as reduced insulin-mediated antilipolytic activity (Kantartzis et al., 2007).
References
Sirito M, Lin Q, Maity T, Sawadogo M. Ubiquitous expression
of the 43- and 44-kDa forms of transcription factor USF in
mammalian cells. Nucleic Acids Res. 1994 Feb 11;22(3):42733
Cogswell JP, Godlevski MM, Bonham M, Bisi J, Babiss L.
Upstream stimulatory factor regulates expression of the cell
cycle-dependent cyclin B1 gene promoter. Mol Cell Biol. 1995
May;15(5):2782-90
Luo X, Sawadogo M. Antiproliferative properties of the USF
family of helix-loop-helix transcription factors. Proc Natl Acad
Sci U S A. 1996 Feb 6;93(3):1308-13
Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder
RG. Cloning of an inr- and E-box-binding protein, TFII-I, that
interacts physically and functionally with USF1. EMBO J. 1997
Dec 1;16(23):7091-104
Implicated in
Carcinogenesis
Sirito M, Lin Q, Deng JM, Behringer RR, Sawadogo M.
Overlapping roles and asymmetrical cross-regulation of the
USF proteins in mice. Proc Natl Acad Sci U S A. 1998 Mar
31;95(7):3758-63
Note
Given the suggestive evidence for a role of USF1 in
tumor suppression, one may anticipate that
carcinogenesis will evolve from loss of USF1
transactivation activity, either as a result of mutations
in the USF1 gene or of posttranslational modification
of USF1 protein. This has not been reported yet.
Alternatively, tumor suppressor genes may lose
responsivity to USF1 by mutations in the DNA binding
element or by changes in local DNA methylation. This
is exemplified by the observation of a classic Cowden
syndrome patient with early onset breast cancer and
reduced PTEN activity, which appears to be due to a
specific germline mutation of an E-box element in the
PTEN gene and loss of USF1 binding (Pezzolesi et al.,
2007).
Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean
M, Kahn A, Vaulont S. Differential roles of upstream
stimulatory factors 1 and 2 in the transcriptional response of
liver genes to glucose. J Biol Chem. 1998 Aug
7;273(32):20175-9
Ismail PM, Lu T, Sawadogo M. Loss of USF transcriptional
activity in breast cancer cell lines. Oncogene. 1999 Sep
30;18(40):5582-91
McMurray HR, McCance DJ. Human papillomavirus type 16 E6
activates TERT gene transcription through induction of c-Myc
and release of USF-mediated repression. J Virol. 2003
Sep;77(18):9852-61
Saito T, Oishi T, Yanai K, Shimamoto Y, Fukamizu A. Cloning
and characterization of a novel splicing isoform of USF1. Int J
Mol Med. 2003 Aug;12(2):161-7
Familial combined hyperlipidemia
(FCHL)
Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ,
Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J,
Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L.
Familial combined hyperlipidemia is associated with upstream
transcription factor 1 (USF1). Nat Genet. 2004 Apr;36(4):371-6
Disease
FCHL is the most common genetic form of
hyperlipidemia and is associated with increased risk of
premature cardiovascular disease. Affected persons
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
Chang JT, Yang HT, Wang TC, Cheng AJ. Upstream
stimulatory factor (USF) as a transcriptional suppressor of
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Verhoeven AJM
human telomerase reverse transcriptase (hTERT) in oral
cancer cells. Mol Carcinog. 2005 Nov;44(3):183-92
Kantartzis K, Fritsche A, Machicao F, Stumvoll M, Machann J,
Schick F, Häring HU, Stefan N. Upstream transcription factor 1
gene polymorphisms are associated with high antilipolytic
insulin sensitivity and show gene-gene interactions. J Mol Med.
2007 Jan;85(1):55-61
Corre S, Galibert MD. Upstream stimulating factors: highly
versatile stress-responsive transcription factors. Pigment Cell
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Naukkarinen J, Gentile M, Soro-Paavonen A, Saarela J,
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and dyslipidemias: converging evidence for a functional
intronic variant. Hum Mol Genet. 2005 Sep 1;14(17):2595-605
Pezzolesi MG, Zbuk KM, Waite KA, Eng C. Comparative
genomic and functional analyses reveal a novel cis-acting
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Rada-Iglesias A, Ameur A, Kapranov P, Enroth S, Komorowski
J, Gingeras TR, Wadelius C. Whole-genome maps of USF1
and USF2 binding and histone H3 acetylation reveal new
aspects of promoter structure and candidate genes for
common human disorders. Genome Res. 2008 Mar;18(3):38092
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combined hyperlipidemia. Curr Opin Lipidol. 2006
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2009 Jul 10;284(28):18851-62
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metastasis suppressor gene promoter by the recruitment of
HDAC1 into a USF1-Sp1-Sp3 complex. J Biol Chem. 2007 Sep
14;282(37):26725-39
Naukkarinen J, Nilsson E, Koistinen HA, Söderlund S,
Lyssenko V, Vaag A, Poulsen P, Groop L, Taskinen MR,
Peltonen L. Functional variant disrupts insulin induction of
USF1: mechanism for USF1-associated dyslipidemias. Circ
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recruits histone modification complexes and is critical for
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Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. A
role of DNA-PK for the metabolic gene regulation in response
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delay in G2/M phase in FRTL-5 cells. Endocr J. 2007
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Atlas Genet Cytogenet Oncol Haematol. 2011; 15(1)
This article should be referenced as such:
Verhoeven AJM. USF1 (upstream transcription factor 1). Atlas
Genet Cytogenet Oncol Haematol. 2011; 15(1):73-76.
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