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. 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, 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, for example as a result of phosphorylation by cyclinE/Cdk2 complexes,, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27^Kip1 and show here that 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.