Transcript 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 • • • • 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 • • • • 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 • • • • 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 • • • • 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 • • • • Molecules mRNA Receptors -Sensitive neurons – Regulates differentiation cholinergic neurons in basal forebrain – Counteracts learning, memory deficits in lesioned animals – Alzheimer’s therapy??