Cell cycle and differentiation

• Exogenous control in multicellular organisms

• Proliferation– Cell type-specific receptors– MAPK (ERK1/2)– b-catenin

• Differentiation– Cell type-specific receptors– MAPK/SMAD– Cell type-specific transcription factors

Cell Cycle

• G0

– Terminal differentiation

• G1

• S– Replication

• G2

• M– Division

CyE/CDK2

CyD/CDK4

CyA/CDK2

CyB/CDK1

Rb, p53,bHLH’s

Id

Proliferation

• Mitogens– 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

• ??ACCREBPaxmyf5/MyoDmyogenic program

MetHGF sensitivity

wnt

• FGF[MAPK]CDK4cell proliferation• HGFcMetcell migration• WntFzdsh--|GSK3--|b-catenin

TCFproliferation

MyoDdifferentiation

Regeneration

• Satellite cells• Repair recapitulates development

– HGFcMet[MAPK]CyD– IGF1[PI3K]--|p27kip– Myostatin[SMAD]--|myoD– Ca2+CnNFAT/MEF2myogenin

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– GSK3 inhibition promotes cell cycle– Fyn/RhoA promote adhesion & FAK– PLC/Cn promote specification