Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1

The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27(Kip1) is an essential participant in this regulation both in vitro and in vivo(1). Although mutations in p27(Kip1) are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas(2), suggesting that disruption of the p27(Kip1) regulatory mechanisms contributes to neoplasia. The abundance of p27(Kip1) in the cell is determined either at or after translation(3), for example as a result of phosphorylation by cyclinE/Cdk2 complexes(4,5), degradation by the ubiquitin/proteasome pathway(6), sequestration by unknown Myc-inducible proteins(7), binding to cyclinD/Cdk4 complexes(8), or inactivation by the viral ElA oncoprotein(9). We have found that a mouse 38K protein (p38) encoded by the Jab1 gene(10) interacts specifically with p27(Kip1) and show here that ol overexpression of p38 in mammalian cells causes the translocation of p27(Kip1) from the nucleus to the cytoplasm, decreasing the amount of p27(Kip1) in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27(Kip1)-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27(Kip1) by promoting its degradation.