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

Kiichiro Tomoda, Yukiko Kubota and Jun-ya Kato ()
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Kiichiro Tomoda: Graduate School of Biological Sciences, Nara Institute of Science and Technology
Yukiko Kubota: Graduate School of Biological Sciences, Nara Institute of Science and Technology
Jun-ya Kato: Graduate School of Biological Sciences, Nara Institute of Science and Technology

Nature, 1999, vol. 398, issue 6723, 160-165

Abstract: Abstract The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo 1. Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas2, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation3, for example as a result of phosphorylation by cyclinE/Cdk2 complexes4,5, degradation by the ubiquitin/proteasome pathway6, sequestration by unknown Myc-inducible proteins7, binding to cyclinD/Cdk4 complexes8, or inactivation by the viral E1A oncoprotein9. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene10 interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-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 p27Kip1 by promoting its degradation.

Date: 1999
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DOI: 10.1038/18230

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