Download Growth Hormones

Growth Hormones
What is Growth?
Growth Hormone (Somatotropin)
Actions of GH
Production of GH
Regulation of GH Release
GH Binding Protein
GH Receptor
Role of Somatomedins & IGF-Binding
Proteins
Other Factors Regulating Growth
What is Growth?

Growth is an increase in size of a tissue/organism
due to
- increase in cell size (hypertrophy)
- increase in number of cells (hyperplasia)
- increase in extracellular matrix around cells
hypertrophy
hyperplasia
Hormones and Growth

A number of hormones influence growth of
specific target tissues:
- FSH; ovary
- ACTH; adrenal
- estrogen; breast, uterus
- TSH; thyroid
- testosterone; prostate gland….
Growth Hormone
(GH; Somatotropin)


The major hormone regulating growth in the
body is growth hormone (GH; somatotropin).
Actions of Growth Hormone:
- increases skeletal growth
- increases muscular growth
- increases amino acid uptake and protein
synthesis
- increased use of lipids for energy
- decreased storage of carbohydrates
Pituitary Dwarfism



Due to lack of GH release from the
pituitary, or lack of GH receptor
expression (or other deficits….)
Results in delayed growth and short stature
(below 5 ft) in adult.
Body development is proportional.
GH and Aging

Some data indicate that GH treatment
may help counteract some effects
associated with aging (loss of muscle
tone, increased body fat).
Structure and Source of Growth Hormone
GH is a large peptide hormone, with 191
amino acids
 GH is produced by somatotroph cells of the
anterior pituitary

Regulation of GH Levels

GH is released from the pituitary in a pulsatile
manner:
hormone
level
time
• GH levels are low during the day, but increase during sleep.
• There is an overall increase in GH levels during puberty.
• Implications for wt loss (circ rhythm and food deprivation).
Control of GH Release



GH is under the control of two hypothalamic
releasing factors, GHRH and somatostatin.
GHRH acts through a Gs protein-coupled receptor to
increase cyclic AMP-dependent protein kinase A
activity.
-Increased PKA activity causes increased levels and
activity of a transcription factor, PIT-1, resulting in
increased GH synthesis and release.
Somatostatin acts through a Gi protein coupled
receptor, decreasing cAMP levels and PKA activity,
and decreasing PIT-1 activity.
Regulation of GH Expression in
Somatotrophs
somatostatin
GHRH
Gs AC Gi
(-)
cAMP
PKA
PIT-1
A txn factor in the Pit
GH synthesis
Phases of Sleep:
REM versus NonREM
Characteristics
Eye movements
Brain activity
Muscle activity
Vital signs
REM Sleep State NREM Sleep State
REM, closed lids
Lacks REM
Active (dreaming)
Resting phase
Bursts of twitching Diminished
Active, irregular
Decreased
Control of GH Release (con’t)




GH release is stimulated by deep (nonREM)
[complete relaxation] sleep, but is inhibited during
REM sleep.
GH release is also stimulated by stress and exercise
 nts (NE, epi)  incr glc from glycogen [activates
phosphorylase in muscle and liver (Cori Cycle)].
Also, epi  lypolysis TGs  FFAs incr metabolism.
GH release is inhibited by elevated glc, and
stimulated by high levels of certain amino acids (arg).
Control of GH Release (cont)
Perhaps the major regulation is achieved by
negative feedback by GH and somatomedins
(IGFs) at the pituitary and hypothalamic
levels.
 Increased GH or IGF levels result in
inhibition of GHRH and stimulation of
somatostatin release. Net result: inhibition
of GH levels.

Growth Hormone Receptor

Growth hormone binds to a receptor that is
closely associated with an intracellular
tyrosine kinase (JAK-2).
Cf., Fig. 12-1
JAK-2
Growth Hormone Receptor
Binding of GH to the receptor results in
phosphorylation of various substrates
within the cell, resulting in a biological
response.
 This triggers a number of pathways:
- Insulin responsive substrates, MAP
kinase
- phospholipase C/IP3/PKC
- induction of fos/jun (AP-1) and myc
expression

Transport of GH in the Blood



About 50% of GH is found in the blood
bound to a Growth Hormone-Binding
Protein (GHBP).
GHBP increases the half-life of GH, but
decreases biological activity (bound GH is
not biologically available).
The GHBP is identical to the ligand
binding domain of the GH receptor, and
may be derived from alternative splicing of
the GH receptor RNA.
GHBP binding site is identical to the GH receptor (GHR) binding site
GH receptor mRNA
GH binding domain (GHBD)
AAAAAA
Alternative splicing
GHBD
GHBD
GHBP
GHR
Relationship between GH Receptor and
GH Binding Protein
extracellular
ligand-binding
region
associated
tyrosine
kinase
(JAK-2)
growth hormone receptor
growth hormone
binding protein
Direct Actions of GH


GH appears to act directly on cells to
cause
– Lipolysis (breakdown of stored fat into
free fatty acids)
– Glycogenolysis (breakdown of
glycogen to form glucose)
Therefore, it makes sense that increased
glucose levels will inhibit GH release.
Role of Somatomedins in GH Actions –
the GH/IGF Axis



The effects of GH on skeletal and muscular growth
appear to be due to the activity of somatomedins,
or insulin-like growth factors (IGF-1 and IGF-2) –
processed in the liver.
GH acts on the liver, and some other tissues, to
increase the production of IGFs.
IGFs then enter the circulation and act on target
tissues to enhance growth.
IGF Receptors



IGFs bind to specific receptors (type-I IGF receptor
and the insulin receptor) to stimulate growth.
The type-I IGF receptor is similar to the insulin
receptor, with intrinsic tyrosine kinase activity.
Binding of IGFs to their receptors results in
phosphorylation of insulin-responsive substrates
(IRSs), which stimulate tissue growth and
differentiation.
extracellular domains
(ligand binding)
plasma membrane
tyrosine kinase
domains
phosphorylation of IRSs
Growth and
differentiation
Some Observations in Knockout Mice:
IGF-II



Gene knockout experiments can create mice
which lack expression of certain genes.
Knockout of IGF-II gene results in slower
fetal development, with low birth weights.
However, after birth these mice grow at
normal rates.
This finding suggests that IGF-II is an
important fetal growth factor, with unclear
role in growth after birth.
Some Observations in Knockout Mice:
IGF-I



Knockout of the IGF-I gene also results in
slow fetal development and low birth
weights.
However, these mice also display marked
lack of growth after birth as well.
Thus, IGF-I is important for growth at all
stages of development (before and after
birth).
Some Observations in Knockout Mice:
GH



Knockout of the GH gene results in normal
fetal growth, and normal birthweight.
However, after birth, growth is impaired.
Together these results indicate that IGF-I
and IGF-II are NOT regulated by GH
during fetal development.
Roles of IGF Binding Proteins



IGFs bind to several (at least ten) IGF binding
proteins (IGFBPs).
Several possible actions of IGFBPs have been
proposed.
Some IGFBPs are believed to inhibit the action of
IGFs by binding them and making them less
biologically available:
IGF
IGFBP
IGF Receptor
Roles of IGF Binding Proteins



Some IGFBPs may also enhance IGF
action (possibly by delivering IGFs to the
cell, or increasing half-life), resulting in
increased stimulation of the IGF receptor.
Also, IGFBPs may act independently of
IGFs. Specific IGFBP receptors have
been observed on cell membranes.
Thus, regulating the expression of
IGFBPs influences IGF activity.
binds
IGFBP
IGF
IGF receptor binding
OR
binds
IGFBP
Receptor
[In liver cell membrane
or cytoplasm]
Txn of proapoptotic
genes
E.g., IGFBP gene is induced by hypoxia  incr expression of
IGFBP and  developmental delay and retardation of embryonic
Growth.
IGFBP Proteases



The activity of IGFBPs is also regulated by
proteases which degrade IGFBPs.
By regulating IGFBPs, these proteases may be
important regulators of IGF bioactivity and
bioavailability.
Specific proteases have been identified for
most IGFBPs.
IGFBP
protease
IGF
IGFBP
Example: Prostate-Specific Antigen



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Prostate cancer: hyperplasia of prostate cells
Normally, the action of IGF-I on prostate cells
is inhibited by binding to IGFBP3.
Patients with prostate cancer have elevated
levels of prostate-specific antigen (PSA),
which is a protease for IFGBP3.
Increased protease levels may result in
increased mitogenic effect of IGF on prostate
cells.
A protease
PSA
IGF
IGFBP3
IGF (mitogen) may now
bind its receptor on
prostate cells and incr
growth of prostate gland
Other Factors Regulating Growth

Recall that estrogen and androgens stimulate skeletal
and muscular growth.
-estrogens (and androgens) act on and maintain bone,
inhibit osteoclast activity
-androgens act on muscle, increasing size (anabolic
steroids)
-estrogens and androgens also stimulate GH release
Other Factors Regulating Growth


Last lecture we saw how vitamin D and PTH
were involved in regulation of bone growth.
Also recall that thyroid hormone is required
for GH synthesis and action:
- TRE on GH gene (effects synthesis of GH)
- T3 induces GH receptor expression
Genetic Factors: Inheritance of Height


The genetic factors responsible for the
inheritance of height are largely unknown.
Identical twins show a high correlation for
height (0.9), but not for weight (0.2)
Effects of Nutrition



There is also an interaction between genetic
factors and nutrition.
Adequate intake of nutrients (ie, vitamins
and minerals) and calories is required to
reach full growth potential, especially
during childhood.
Recall that arginine (an amino acid)
stimulates GH release.
food
vitamins, minerals,
calories from lipids,
carbohydrates, and
proteins
growth
GH
Other Growth Factors:
Fibroblast Growth Factor (FGF)

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Several forms of FGFs exist (acidic, basic,
etc.)
FGFs act as local regulators of growth and
differentiation (autocrine/paracrine
function).
A number of FGF receptors have been
identified.
FGFs stimulate the development of organs
and of bone.
Epidermal Growth Factor (EGF)





EGF is named after its stimulatory effect on
skin cell proliferation.
EGF appears to play a role in development and
growth.
Associated with eyelid development (in
species born with closed eyelids), and eruption
of teeth.
EGF acts through the intrinsic tyrosine kinase
activity of its receptor.
Interestingly, knockout of EGF has little effect
on growth. Redundant mechanisms must
exist.
Nerve Growth Factor (NGF)

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NGF appears to be important in survival of
neurons, and in the innervation of target
tissues.
Acts through a tyrosine kinase activity.
Also, NGF acts as a IGFBP-3 protease,
increasing the influence of IGFs on nerve
cells.
May be important in recovery from damage to
nervous tissue.
Inhibitory Growth Factors


Transforming growth factor alpha (TGFa):
local factor which can act to both stimulate
cell growth as well as inhibiting cell growth,
depending upon the situation.
Tumor Necrosis Factor (TNF): Inhibits
growth of tumor and other cells by initiating
programmed cell death.
Next Time
Second Midterm Exam
Includes material starting at the
lecture after the first midterm
(end of steroid receptor lecture)
and through today’s lecture.