Cell cycle and differentiation Exogenous control in multicellular organisms Proliferation Cell type-specific receptors MAPK (ERK1/2) b-catenin Differentiation MAPK/SMAD Cell type-specific transcription factors

Cell Cycle G0 G1 S G2 M Terminal differentiation Replication Division Rb, p53, bHLH’s CyB/CDK1 Id CyD/CDK4 CyA/CDK2 CyE/CDK2

Proliferation Mitogens DNA synthesis Cell size integration FGF, EGF, HGF DNA synthesis CyD/CDK4 accumulation Degradation of Rb Activation of E2F Cell size integration GSK3 inhibits CDK4 GSK3 inhibits b-Catenin

Differentiation bHLH transcription factors Class A/general TCF Class B/Tissue specific MyoD Twist Hairy b-Catenin: bHLH-HDAC deactivator Inhibitor of differentiation (Id) HLH, no b No b = no DNA binding

Myogenesis GF-dependent commitment

Transcriptional cascades ??ACCREBPax myf5/MyoDmyogenic program MetHGF sensitivity wnt FGF[MAPK]CDK4cell proliferation HGFcMetcell migration WntFzdsh--|GSK3--|b-catenin TCFproliferation MyoDdifferentiation

Regeneration Satellite cells Repair recapitulates development HGFcMet[MAPK]CyD IGF1[PI3K]--|p27kip Myostatin[SMAD]--|myoD Ca2+CnNFAT/MEF2myogenin

Proliferation-differentiation competition Rb/E2F Rb/E2F dimers repress S-phase proteins E2F activates S-phase proteins Rb/Id Rb/Id dimers bind MyoD & activate HDAC Rb/Id activates differentiation TCF/MyoD TCF/b-catenin promotes cell cycle MyoD/b-catenein promotes differentiation

Crosstalk between hypertrophy and hyperplasia PI3K mTOR increases protein synthesis FOXO inhibition prevents apoptosis GSK3 inhibition promotes cell cycle Dsh Fyn/RhoA promote adhesion & FAK PLC/Cn promote specification