Lecture #11: Growth Hormones and Growth Factors
I. INTRODUCTORY REMARKS
1. Mammalian cells have characteristic growth cycles: (Fig. 12.1)
a. "G0" is the resting phase.
b. "G1" is a growth phase preparatory to the synthetic phase (S).
c. "S" is the interphase, or synthetic phase, when DNA is duplicated.
d. "G2" is a short period (4-5 hours) when protein synthesis occurs before mitosis.
e. "M" is the complex phase of mitosis.
2. Daughter cells may:
a. re-enter the cycle (e.g., stem cells of bone, GI epithelial cells, spermatogonia)
b. become dormant (resting) (e.g., fibroblasts, osteocytes, memory cells of immunity.
c. become fully mature cells (e.g., skeletal muscle cells, neurons, RBCs, PMNs, spermatozoa).
3. Hormones are the principal stimulant for tissue and organ growth (hypertrophy/atrophy).
4. Principal control point is probably at the transition from Go to G1.
5. Growth of tissue may occur as a result of:
a. cell enlargement (hypertrophy)
b. cell multiplication (hyperplasia)
c. intercellular secretions (e.g., formation of extracellular matrix)
II. SOMATOTROPIN (STH, or GH) AND THE SOMATOMEDINS (IGFs)
1. STH causes growth of the epiphyseal regions of the long bones and growth of connective tissues.
2. STH receptor is somewhat homologous to the insulin receptor (JAK2 and STAT protein) (Fig. 12.9)
2. STH acts indirectly by producing sulfation factor(s) from liver (and elsewhere) = somatomedins.
3. Somatomedins (i.e., somatotropin-mediating agents) have insulin-like properties.
a. IGF-I
and IGF-II have peptide
sequences similar to insulin. (Fig.
12.2)
b. all evolved from one ancestral hormone that probably regulated both metabolism and growth.
(i) insulin’s primary function is glucose metabolism and cell differentiation.
(ii) growth factors primarily promote mitosis and cell proliferation.
c. there are different, primary receptors for each, but they have considerable cross-reactivity.
4. IGF receptors are structurally related to the insulin receptors. (Fig. 12.3)
a. a-subunits lie entirely extracellularly and contain cysteine-rich regions.
b. b-subunits are toward inside of cell, sharing 85% homology with insulin receptor in Ktyr domain.
c. IGF-I receptor autophosphorylates in the Ktyr domain when an IGF (mainly IGF-I) binds to it.
(i) this leads to activation of insulin-responsive substrate (IRS).
(ii) IRS activates PKB and mitogen-activated protein kinase (MAPK).
d. IGF-II receptor is different, i.e., it is homologous to the human mannose-6-phosphate receptor.
5. By negative feedback, IGFs
stimulate hypothalamic SS, while inhibiting STH secretion (Fig.
12.5)
6. For summary of STH action, see Fig. 12.6. (NOTE: For more detail on IGFs, click HERE.)
III.
INSULIN
1. Besides its role in glucose homeostasis, it also has a profound effect on growth processes.
2. Insulin is required for the full anabolic effects of STH (it provides glucose & amino acids).
IV. PROLACTIN
1. Remember that PRL and STH are structurally similar, so PRL has growth effects.
2. The difference is that PRL is usually associated with reproductive tissue growth.
3. Along with its effect on mammary tissue it affects growth and function of gonads.
4. PRL also stimulates production of IGFs in the liver.
1. Syncytiotrophoblastic cells in the embryo produce chorionic somatomammotropin which promotes lactogenic activity, and therefore is called placental lactogen (PL).
2. PL and STH both have 191 AAs, which are identical throughout 85% of their structure.
3. PL increases during the last half of pregnancy, to prepare mammary tissue for lactation.
4. PL might also function to promote general growth of the fetus.
VI.
NERVE
GROWTH FACTOR(s)
1. The name is appropriate since NGF promotes peripheral nerve differentiation and growth.
2. It is also abundant in submandibular salivary glands of male mice & in snake venom.
3. There is structural homology and functional similarity with proinsulin.
4. NGF is a complex with a-, b-, and g-subunits (with only the b-subunit having activity).
5. NGF is essential for normal growth and life-long function of sympathetic post-ganglionic neurons. (Remember? These secrete norepinephrine.)
6. It stimulates synthesis of tyrosine hydroxylase and dopamine hydroxylase to promote catecholamines.
7. In mice, it causes hypertrophy of the adrenal medulla, which secretes catecholamines.
8. Other neurotrophins include brain-derived neurotrophic factor (BDNF) and neurotrophins-3 and -4.
VII. OTHER PEPTIDE GROWTH FACTORS
A. ERYTHROPOIETIN [erythropoietin] (poietin =
to make)
1. This erythrocyte-stimulating factor has properties of a growth factor.
2. Its release from kidney (and liver) is promoted by tissue hypoxia. [hypoxia] (Fig. 12.14)
3. EPO (or, EP) enhances proliferation of erythrocyte precursor cells in bone marrow.
4. EPO promotes the synthesis of 2.3 million RBCs/sec.
5. EPO has a
half-life of 5 hours, and it requires 2-3 days to cause a
detectable increase in RBCs.
B. PLATELET-DERIVED GROWTH FACTOR
1. PDGF is released from granules of platelets during blood clotting.
2. At site of injury, it may promote contraction of injured vessels to reduce flow.
3. It may also promote conversion of fibroblasts to myofibroblasts to aid in wound healing and in the formation of new arterial walls. (angiogenesis).
C. EPIDERMAL GROWTH
FACTOR (53 AAs) (Fig.
12.19)
1. EGF enhances cell proliferation in basal layer of skin (tooth eruption, eye opening).
2. EGF is abundant in submaxillary, in association with arginine esterase binding protein.
3. It is suggested that licking wounds introduces EGF to promote skin proliferation.
4. Urogastrone is the human form of EGF:
a. named because it was found in pregnant urine, and reduced gastric ulcers by ↓ gastric HCl.
b. also has 53 AAs, with 37 being homologous to mouse EGF.
c. both stimulate DNA synthesis in human fibroblasts, open eyes of mice, etc.
d. both urogastrone and EGF stimulate the same receptors on fibroblasts.
D. GROWTH FACTORS
THAT PROMOTE ANGIOGENESIS
1. Fibroblast growth factor is a family of acidic and basic FGFs. (140-146 AAs)
a. FGFs have a wide range of effects on many cells.
b. FGFs promote angiogenesis and mitosis in epithelia, mesenchyme (i.e., skeletal, circulatory, immune, and connective tissues) and neurons.
c. FGFs have roles in development, neuron maintenance, and wound healing.
d. Its high degree of structural conservation through species suggests that it has a very fundamental (or primordial) role in the course of evolution.
2. Vascular endothelial growth factor (VEGF) is important in angiogenesis.
E. TRANSFORMING GROWTH FACTOR FAMILY (a- and b-types)
a. TGF-a (50 AAs) has sequence homology with EGF and binds to EGF receptor. (It is good in antibiotic creams to promote wound healing.)
b. TGF-b (112 AAs), like inhibin and Mullerian regression factor (MRF), inhibits proliferation of most cells except for fibroblasts. (Is it an example of a chalone, i.e., a mitogenesis inhibitor???)
E. THYMOSINS are secreted by the thymus, and stimulate maturation of immune cells.