A Pathway in Quiescent Cells That Controls P27Kip1 Stability, Subcellular Localization, and Tumor Suppression

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2006 Jan 5

PMID 16391232

Citations 115

Authors

Arnaud Besson

Mark Gurian-West

Xueyan Chen

Karen S Kelly-Spratt

Christopher J Kemp

James M Roberts

Affiliations

Soon will be listed here.

Abstract

We have created two knock-in mouse models to study the mechanisms that regulate p27 in normal cells and cause misregulation of p27 in tumors: p27(S10A), in which Ser10 is mutated to Ala; and p27(CK-), in which point mutations abrogate the ability of p27 to bind cyclins and CDKs. These two mutant alleles identify steps in a pathway that controls the proteasomal degradation of p27 uniquely in quiescent cells: Dephosphorylation of p27 on Ser10 inhibits p27 nuclear export and promotes its assembly into cyclin-CDK complexes, which is, in turn, necessary for p27 turnover. We further show that Ras-dependent lung tumorigenesis is associated with increased phosphorylation on Ser10 and cytoplasmic mislocalization of p27. Indeed, we find that p27(S10A) is refractory to Ras-induced cytoplasmic translocation and that p27(S10A) mice are tumor resistant. Thus, phosphorylation of p27 on Ser10 is an important event in the regulation of the tumor suppressor function of p27.

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