p21Cip1 promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export

Abstract

There is increasing evidence that p21Cip1 and P27Kip1 are requisite positive regulators of cyclin D1-CDK4 assembly and nuclear accumulation. Both Cip and Kip proteins can promote nuclear accumulation of cyclin D1, but the underlying mechanism has not been elucidated. We now provide evidence that p21Cip1 promotes the nuclear accumulation of cyclin D1 complexes via inhibition of cyclin D1 nuclear export. In vivo, we demonstrate that p21Cip1 can inhibit glycogen synthase kinase 313-triggered cyclin D1 nuclear export and phosphorylation-dependent nucleocytoplasmic shuttling. Furthermore, we find that cyclin D1 nuclear accumulation in p21/p27 null cells can be restored through inhibition of CRM1-depenendent nuclear export. The ability of p21Cip1 to inhibit cyclin D1 nuclear export correlates with its ability to bind to Thr-286-phosphorylated cyclin D1 and thereby prevents cyclin D1-CRM1 association.