Growth hormone, growth factors, & growth-related diseases Flashcards
Growth hormone
Growth hormone: a specific polypeptide hormone released into circulation by ant. pit.
somatotroph cells, acts on target cells in the periphery (e.g., in adipose, muscle, bone, liver)
Growth factors
a broad/general term often used to mean secreted factors that stimulate
growth (cell proliferation and/or differentiation)
Cytokines
a broad/general term for small proteins with cell signaling functions. They have a
fundamental role in the immune system; are typically short-lived and act locally; and a specific
cytokine may often be produced by multiple cell types
Broad range of functions (which may include promoting growth), but historically
categorized as cytokines when exerting immunological or hematopoietic responses
Hormones, growth factors, and cytokines: …
all chemical messengers/signaling molecules that bind to specific receptors, initiating signal transduction pathways and biological responses
Growth factors and cytokines have some similarities in structure to ___ hormones; they also act on cell ___ receptors (and receptors have structural homologies);
might share ____ signaling components
• Growth factors and cytokines have some similarities in structure to peptide hormones;
they also act on cell surface receptors (and receptors have structural homologies);
might share downstream intracellular signaling components
Growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis
GH
191-a.a. polypep@de hormone synthesized by anterior pituitary somatotroph cells; ~ half in circulaNon is bound to specific GH-binding proteins (GHBP) (reduce oscillaNons, prolong half-life) • High-affinity GHBP is the same as the extracellular porNon of GH receptor
Growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis
IGF-1
70-a.a. polypep@de hormone
synthesized by many Nssues
(paracrine/autocrine signaling), and most
IGF-1 in circula@on (endocrine signaling) is
produced by liver; bioavailability is
determined by specific IGF binding proteins
Growth hormone (GH) signaling
• GH:
• GH: linked to nutritional status; promotes
↑ lean mass & using lipid/carbohydrate stores
Most growth-promoting effects of GH are
mediated by IGF-1 (“indirect” effect of GH)
- GH stimulates liver to produce IGF-1 (into
circulation), and stimulates local (autocrine
/paracrine) IGF-1 production by most tissues - Well-known effects in bone & skeletal muscle
GH also has ____
GH also has metabolic effects
Growth hormone (GH) signaling Liver
Liver: stimulates glucose release (energy
source), in addition to release of IGF-1
• White adipose tissue: stimulates lipolysis and
release of fatty acids (energy source), while
inhibiting uptake of lipids from circulation
• w/IGF-1, promotes protein accumulation
(increases a.a. uptake & protein synthesis)
GH: linked to nutritional status . fasting _____, potentially to mobilize lipids as an energy source & prevent protein loss
• GH: linked to nutritional status – fasting
stimulates GH secretion, potentially to mobilize
lipids as an energy source & prevent protein lo
ghrelin
• e.g., via ghrelin, the “hunger hormone”
produced by enteroendocrine cells of GI tract,
which binds to receptors on somatotroph
cells and potently stimulates GH secretion
- Rise in glucose or free fatty acids = ___ GH
- Protein-high meal or a.a. infusion = __ GH release
- Stress, exercise, and sleep all lead to ___ GH
- Rise in glucose or free fatty acids = ↓ GH
- Protein-high meal or a.a. infusion = ↑ GH release
- Stress, exercise, and sleep all lead to ↑ GH
Age affects GH levels (___ levels in children,
drops in adulthood)
Age affects GH levels (high levels in children,
drops in adulthood)
Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor
step 1
- Different portions of a single GH associate with two independent GHR, leading to JAK2 recruitment
Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor
step 2
2. JAK2 undergoes autophosphorylation & phosphorylates the GHR, providing a docking site for a STAT (signal transducers and activators of transcription).
Growth hormone (GH) signaling – GH receptor is a Type 1 cytokine receptor
step 3
3. STAT is then phosphorylated by JAK2, and can form dimers that translocate to the nucleus and regulate transcription of its target genes (e.g., stimulates IGF-1 gene expression).
Thyroid hormone:
promotes GH secretion and GH’s growth & metabolic effects;
Hypothyroidism in children leads to reduced growth after birth & developmental delays
Gonadal sex steroids
• Gonadal sex steroids: important for puberty growth spurt
Estradiol stimulates IGF-1 production and also promotes GH secretion
Glucocorticoids : high levels can \_\_\_ growth (due to \_\_\_ endogenous levels/hypersecretion,
\: high levels can suppress growth (due to excess endogenous levels/hypersecretion,
Synergistic actions of hormones
e.g., growth hormone (GH) &
thyroid hormone (TH)
Synergistic actions of hormones
e.g., growth hormone (GH) &
thyroid hormone (TH)
e.g., Cushing syndrome, or due to exogenous glucocorticoids, e.g. steroid treatments); Glucocorticoids \_\_\_\_ somatostatin secretion
e.g., Cushing syndrome, or due to exogenous glucocorticoids, e.g. steroid treatments); Glucocorticoids increase somatostatin secretion
Acromegaly
- excess GH (and therefore high IGF-1) after puberty
- Most often because of excessive GH secretion (e.g., GH-secreting pituitary adenomas)
Growth hormone axis deficiency
Abnormalities at various levels of the axis
GH deficiency
(GH gene defect, pituitary defect, hypothalamic dysfunction)
– therefore, low levels of IGF-1
Laron syndrome
: GH resistance, or deficiency in GH receptor (and GH binding protein),
or IGF-1 or IGF-1 receptor defect – any could result from gene mutations
GH levels are ___ under GH resistance, but IGF-1 levels are ____;
low IGF-1 levels mean lack of ___ feedback inhibition, and ∴ ___ in circulating GH
GH levels are elevated under GH resistance, but IGF-1 levels are low or absent;
low IGF-1 levels mean lack of negative feedback inhibition, and ∴ rise in circulating GH
Other factors that affect growth
Genetics affect height in adulthood
• Nutritional and socioeconomic factors
Malnutrition is a major player that can cause significant endocrine changes
e.g., elevated GH levels but GH resistance (e.g., ↓ GH receptors) and decreased IGF-1
• Chronic disease
Many chronic systemic diseases interfere with growth
• Psychological factors
Psychological stress or psychiatric disease can affect endocrine function or nutrition
Placenta
: endocrine organ that is critical for fetal growth
• Supplies nutrients and oxygen
• Produces & releases many hormones and growth factors
• Insulin-life growth factors (IGFs)
• Insulin-life growth factors (IGFs) are important for fetal growth, but
IGF-1 in the fetus is regulated by metabolic factors other than GH (few GH receptors)
IGF-2
• IGF-2 is more abundant during fetal life than IGF-1
Insulin
• Insulin also has important stimulatory effects on fetal growth
Growth factors
a broad/general term often used to mean secreted factors that stimulate
growth (cell proliferation and/or differentiation)
Growth factor receptor
: the enzyme tyrosine kinase is part of the receptor…
_____ of tyrosine residues in receptor creates docking sites to
recruit adaptor proteins & effectors (forming a ____);
And phosphorylating docked proteins
(e.g., other kinases)
regulates their enzymatic activity,
causing a ________
Autophosphorylation of tyrosine residues in receptor creates docking sites to
recruit adaptor proteins & effectors (forming a signaling complex);
And phosphorylating docked proteins
(e.g., other kinases)
regulates their enzymatic activity,
causing a phosphorylation cascade
Insulin-like growth factors (IGF-1 & IGF-2):
Both are in the same family of peptides as insulin (common ancestral gene)
IGF-1 receptor and insulin receptor are highly homologous,
with many similarities in downstream signaling pathways
Too little growth factor might cause ____ (= children’s weight or rate of weight gain
is significantly below that of other children of similar age and sex)
Too little growth factor might cause failure to thrive (= children’s weight or rate of weight gain
is significantly below that of other children of similar age and sex)
• Proto-oncogenes
normal genes that affect cell growth, but can become oncogenes
(genes with the potential to cause cancer) when something goes awry
• e.g., mutation in a growth factor gene, its receptor,
or a component of its signaling cascade
Therefore, one disease that is associated with too much growth factor is ___
Therefore, one disease that is associated with too much growth factor is cancer
…and tumors can cause increased secretion of growth factors
