I. Perez-roger et al., Cyclins D1 and D2 mediate Myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1), EMBO J, 18(19), 1999, pp. 5310-5320
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.