Growth Hormones

What is Growth?Growth Hormone (Somatotropin)

Actions of GHProduction of GH

Regulation of GH ReleaseGH Binding Protein

GH ReceptorRole of Somatomedins & IGF-Binding Proteins

Other Factors Regulating Growth

hypertrophy

hyperplasia

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

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:

hormonelevel

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

GHRH

ACGs

cAMP

PKA

PIT-1 GH synthesis

Gi(-)

somatostatin

A txn factor in the Pit

Characteristics REM Sleep State NREM Sleep State Eye movements REM, closed lids Lacks REM Brain activity Active (dreaming) Resting phase Muscle activity Bursts of twitching Diminished Vital signs Active, irregular Decreased

Phases of Sleep: REM versus NonREM

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).

JAK-2

Cf., Fig. 12-1

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

Growth Hormone Receptor

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

AAAAAAGH binding domain (GHBD)

Alternative splicing

GHBD GHBD

GHBP GHR

Relationship between GH Receptor and

GH Binding Protein

associatedtyrosinekinase

growth hormone receptor

extracellular ligand-binding region

growth hormonebinding protein

(JAK-2)

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.

phosphorylation of IRSsGrowth anddifferentiation

plasma membrane

extracellular domains(ligand binding)

tyrosine kinase domains

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:

IGFIGFBP

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.

IGFBP

binds IGF IGF receptor binding

OR

bindsIGFBP

Receptor [In liver cell membrane

or cytoplasm]

Txn of proapoptoticgenes

E.g., IGFBP gene is induced by hypoxia incr expression of IGFBP and developmental delay and retardation of embryonicGrowth.

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

IGFIGFBPprotease

Example: Prostate-Specific Antigen

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.

IGFBP3

IGFPSAA protease cleaves

IGF (mitogen) may nowbind its receptor onprostate cells and incrgrowth 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.

vitamins, minerals,calories from lipids,carbohydrates, andproteins

food

growth

GH

Other Growth Factors:Fibroblast Growth Factor (FGF)

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)

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 (TGF): 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.