Cyclins D1 and D2 mediate Myc-induced proliferation via sequestration of p27Kip1 and p21Cip1

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Abstract
Cyclin E–Cdk2 kinase activation is an essential step in Myc‐induced proliferation. It is presumed that this requires sequestration of G1 cell cycle inhibitors p27 Kip1 and p21 Cip1 (Ckis) via a Myc‐induced protein. We provide biochemical and genetic evidence to show that this sequestration is mediated via induction of cyclin D1 and/or cyclin D2 protein synthesis rates. Consistent with this conclusion, primary cells from cyclin D1−/− and cyclin D2−/− mouse embryos, unlike wild‐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 restored by retroviruses expressing either cyclins D1, D2 or a cyclin D1 mutant forming kinase‐defective, Cki‐binding cyclin–cdk complexes. The sequestration function of D cyclins thus appears essential for Myc‐induced cell cycle progression but dispensable for apoptosis.