Figure 6.

Pathways of TGF-β mediated G₁ arrest. In cells containing an inducible p15^INK4b or down-regulated CDC25A gene, cyclin D:Cdk4/6 complexes are targeted for inactivation by TGF-β signaling. In HepG2 cells, the inability of TGF-β to induce p15^INK4b or down-regulate CDC25A levels results in continued cyclin D:Cdk4/6 activity because of presumed continued Cdk4/6 CAK activity. However, cyclin E:Cdk2 complexes are inactivated because of down-regulation of Cdk2 CAK activity. Cyclin D:Cdk4/6 complexes activate the pRB in early G₁ by hypo-phosphorylation (8–10). Cyclin E:Cdk2 complexes perform the initial inactivating hyper-phosphorylation of pRb at the late G₁ restriction point transition (8–10).