Cyclins D1 and D2 mediate Myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1)

Cyclin E-CdK2 kinase activation is an essential step in Myc-induced prolife ration. It is presumed that this requires sequestration of G(1) cell cycle inhibitors p27(Kip1) and p21(Cip1) (Ckis) via a Myc-induced protein. We pro vide biochemical and genetic evidence to show that this sequestration is me diated via induction of cyclin D1 and/or cyclin D2 protein synthesis rates. Consistent with this conclusion, primary cells from cyclin D1(-/-) and cyc lin D2(-/-) mouse embryos, unlike mild-type controls, do not respond to Myc with increased proliferation, although they undergo accelerated cell death in the absence of serum. Myc sensitivity of cyclin D1(-/-) cells can be re stored by retroviruses expressing either cyclins D1, D2 or a cyclin D1 muta nt forming kinase-defective, Cki-binding cyclin-cdk complexes. The sequestr ation function of D cyclins thus appears essential for Myc-induced cell cyc le progression but dispensable for apoptosis.