Download GROWTH

GROWTH
Fetal Development
• Cells grow, differentiate  specific organs
• Genes turned on, off
– Regulate cell structure, function
• Cell life cycle
– G0 – not committed to cell division
– G1 – preparatory to cell division
– S – DNA replicated
– G2 – some protein synthesis
– M – cell division
Growth
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Hypertrophy
Hyperplasia
Incr’d cell molecules
Hormones
– Materials avail to cells
– Stim cell division
– Stim secr’n
– Commonly promote growth
• Absence  atrophy
Growth Hormone
• Secr’n from somatotrophs
– GHRH stims
• Episodic
• If continuous  downreg’n GHRH receptors,
blunted response
– SST inhibits
Somatotroph Receptors
• GHRH  ad cyclase  cAMP  PKA,
and  PLC    IP3, DAG, Ca+2
– Expr’n induced by normal cortisol levels
• SST  inhib’n ad cyclase
– Receptor G-prot coupled, heptahelical
– Gen’l turn-off response (secr’n, cell prolif’n,
etc)
Growth Hormone
• Expression GH gene enhanced
– PROP-1 (related to function of Pit-1)
– cAMP in somatotrophs
• Coactivators of expression
– Normal cortisol levels
– Normal thyroid hormone levels
• 40-50% complexed to GH-BP
– Cleaved extracell domain of GH receptor
– Not avail to receptors (hormonal reservoir)
GH Receptor
• Hematopoietic receptor superfamily
• 3 domains
– Extracell binding
– Single transmembrane segment
– Intracell
• Single GH binds 2 receptors (dimerization)
– Activates Jak-STAT pathway
• Highly species specific
GH Function Discovered @ Bones
• Indirect stim’n growth of epiphyseal region
– Stim’n prolif’n
• Cartilage cells (epiphyseal growth plate)
• Fibroblasts
• Periosteum cells
– After epiphyseal closure, periosteum/
perichondrial growth only
– Increased bone mass, bone mineral density
• Through “sulfation factor”
Somatomedins = Insulin-Like
Growth Factors
• In plasma
• Controlled by GH
• Promotes inc’n sulfur
– Cartilage
– Skeletal, other connective tissues
– Organs
Dual Effector Theory
• GH directly stim’s differentiated state of some
cells
–  New cells more sensitive to IGFs
– Book: GH injected into bone growth plate 
bone growth
• Incr’d # local IGF-I immunoreactive cells w/in
chondrocytes
• Diff cell targets for GH, IGF
– GH stim’s cell division of stem-cell like cells 
clonal expansion
– Then IGF-I enhances initiated clonal expansion
IGF-I, II
• Structure
– 3D sim to insulin
• Gene duplication  2nd chromosome?
•  Funct’l division?
• Some affinity for ins receptor
– Single chain
• I – 70 aa’s
• II – 67 aa’s
• Secr’n I dependent on GH
• II more abundant in human adult plasma
IGF Binding Protein
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150 kDA
Complexes most IGF’s in plasma
GH-dependent
Prod’d by liver
– 6 diff prot’s expressed in diff tissues
– IGF-BP3 binds most IGF
• Acid-Labile Subunit
– Glycoprot
– Interacts w/ IGF-BP-3
Table II
Functional characteristics of human IGFBP
IGFBP
Potential functions
Cell surface/
matrix binding
Modification by
proteolysis
1
Minor serum carrier
Potentiates/inhibits IGF action
Yes
Yes
2
Minor serum carrier
Potentiates/inhibits IGF action
No
Yes
3
Minor serum carrier
Yes
Potentiates/inhibits IGF action
Independent modulator of cell proliferation
Yes
4
Inhibits IGF action
No
Yes
5
Potentiates/inhibits IGF action
Yes
Yes
6
Potentiates/inhibits IGF action?
No
Possible
7
Inhibits IGF action
Unknown
Unknown
• May interact w/ target cells
– Some bind to cell surfaces
– Facilitate hormone/receptor interaction?
– More dynamic than “hormone sink”
Plasma IGF-I
• Incr’s from birth
• Peaks in pre/early adolescent
– Impt to prepubertal growth spurt
– Accompanied by incr’d urinary GH
• Slowly decreases
• Negatively feedback inhibits GH secr’n
– Normally hypersecr’n prevented by rise in
circ’ng IGF-I
• Set-point of neg feedback elevated during
puberty
– Estradiol may re-set by stim’ng hypothal E2
receptors  GHRH effect
– BUT no change in sex steroid prod’n
correlates w/ IGF-I, GH decline
Thyroid Hormones Impt to Growth
• Nec to maintain GH prod’n
– Permissive: GH causing IGF-I stimulation
– Permissive: IGF-I growth promotion
• Paracrine/autocrine functions also
– IGF gen’d @ physio levels at diff tissues
IGF Receptors
• IGF-I
– Ligand-dependent tyr kinase activity
– Autophosphorylation
– Sim structure, function as insulin receptor
• Heterotetramer
• May form hybrid tetramers w/ ins receptor
– IGF-I > IGF-II >> insulin
• Ins receptor binding insulin > IGF-II > IGF-I
• IGF-II
– Does not bind insulin
– Impt to clearing IGF-II from ECF
Functional consequences of IGF-I receptor b subunit activation.
Binding sites for intracellular signaling molecules are indicated. Assignment of
functions to specific phosphotyrosines is described in the text. Dotted areas in the
extracellular a subunit indicate the cysteine-rich domains; dashed areas in the
intracellular b subunit indicate the tyrosine kinase domains. IRS-1, insulin receptor
substrate-1;
GAP, GTPase-activating protein.
Downstream targets of IGF-1R.
Schematic diagram showing the proposed signaling pathways for the
IGF-1R (see details in the text). The crosstalk with other growth
factor tyrosine kinase receptors is not shown. The 85 kDa and 110
kDa subunits of the phosphatidylinositol-3 kinase are shown as p85
and p110.
Table III
Summary of SH2-containing proteins that bind to
IRS-1 or IGF-1
Protein
Function
Specificity
Grb-2/Grb-10
Adapter, binds mSos; Grb-2-mSos
complex activates p21ras
IRS-1, IGF-1R
GAP
Ras GTPase-activating protein
IGF-1R
SH-PTP2(Syp)
Protein tyrosine phosphatase
IRS-1, IGF-1R
p85
Regulatory subunit of the PI 3-kinase
IRS-1, IGF-1R
Nck
Adapter protein; unknown function
IRS-1
Shc
Adapter protein, can bind to the
Grb-2-mSos complex
IRS-1, IGF-1R
Other GH Activities
• Diabetogenic (opposes insulin, IGF)
– Stim’s lipolysis  decr’d glu metab and
 substrates for glu form’n
–  Incr’d plasma FFA  hepatic glu output
–  Incr’d muscle mass (abused)
– Requires glucocorticoid permissive action
– Depletes triglyceride stores of adipocytes
– Protects against hypoglycemia in adults
• Inhibits differentiation of preadipocytes to
adipocytes
• Stim’s prod’n fibrinogen in liver
– Contributes to atherosclerosis,
thromboembolism
– W/ hyperglycemia, hyperlipidemia
• Affects connective tissue of skin
– Physio regulation hair follicles, sweat glands
• Brain effects
– Transported
– Reaches brain via CSF
– Apparent growth factor-like
Insulin Role in Growth
• Book: children of diabetic mothers
(hyperinsulinemic) have incr’d stature
• Req’d for full anabolic effect of GH
– Glu uptake incr’d w/ insulin  energy for prot
synth
– Aa uptake incr’d w/ insulin  incr’d prot synth
– Act’n translation capacity w/ insulin
– Can bind IGF receptors @ high concent
Prolactin Role in Growth
• Sim structure as GH
• Gene expr’n of both regulated by Pit-I
– Pituitary-specific transcription factor
– Also impt to TSH b-subunit expr’n
– Mutation  deficiency almost all ant pit
hormones
• Receptors sim
– Probably not tyr kinase related
• Impt to growth/dev’t mammary glands
– With estrogens, glucocorticoids
• Directly affects growth, function of gonads
– Modulation effects of LH/FSH ??
• Effects immune system
– Lymphocyte growth factor
– Accelerates T-cell-dependent responses
• Impt in amphibian growth
– Tail, gill growth
– Limb regeneration
Nerve Growth Factors
• Impt to central, peripheral NS cell
differentiation, growth
• Reciprocal actions of periph neurons/
target tissues
– Periph tissues  biochem’s enhancing
growth/diff’n of nearby neurons
• May stim innervation of tissues
– Neurons  biochem’s impt to dev’t target
tissues
NGF
• Released by mouse tumor  hypertrophy
chick ganglia
• Prod’d in salivary gland
– High concent
– Regulated by sex steroids
– Impt to fighting
• Peripherally prod’d crucial to ANS periph
symp postganglionic neurons
– Fetal: animal symp ns completely dependent
– Adult: maintenance of symp ns
• Repair, regeneration, protection of neurons
Mouse Salivary NGF
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Used for study
3 polypeptide chain types (a, b, g)
Dimers held by covalent bonds
Synth’d as proNGF
 g is endopeptidase
 a impt to structural maintenance in secretory
granule (?)
 b -- nerve growth promoting activity
• Homologous to insulin
– Similar activities
– Binding to cell membr  enhanced
anabolism (cell growth)
– May have evolved from proinsulin gene
• NGF Receptors
– Two types, perhaps diff functions
• High affinity binding may require both types
• Binding TrkA receptor  act’n receptor tyr
kinase  sev signaling cascades
– PLC/DAG/IP3/PKC
– Ras-mediated act’n of map kinase
• Shc/Grb-2/Sos-1
• Raf/Mek/Erk
• Fos+jun  AP-1 (transcr’n factor)
– Other factors: Egr, CREB
• Impt to neurite form’n, survival symp neurons
NGF Effects
• Synth specific enz’s nec to catecholamine
synth
– Tyr hydroxylase
– DA b-hydroxylase
• Stim nerve fiber outgrowth
– Neurofilaments in axons
• Through posttranslational process
– Ornathine decarboxylase impt?
• Key in polyamine biosynth
• Impt to cell division/growth regulation
• Directs growing symp nerve fibers toward
target tissues
– In fetal dev’t, correlation between [NGF],
mRNA for nerve fiber prot’s, density nerve
fiber prot’s
– Synth’d by many cells
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Epithelia
Smooth muscle cells
Fibroblasts
Schwann cells
– Not mitogenic
– Contued exposure essential to survival in
some cell pop’ns
Figure 4. The nerve growth cone is located in the distal chip of a growing axon and its
movement plays an important role in axon elongation and guidance (left). When the
nerve growth cone receives repulsive stimuli, it becomes collapsed (right) and the axon
stops growing to the direction.
• Neurotropic in mammalian CNS
– Brain NGF
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Molecules
mRNA
Receptors
-Sensitive neurons
– Regulates differentiation cholinergic neurons
in basal forebrain
– Counteracts learning, memory deficits in
lesioned animals
– Alzheimer’s therapy??