Current Biology
Volume 11, Issue 4, 20 February 2001, Pages 263-267
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Brief communication
PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2

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Abstract

The PTEN tumor suppressor acts as a phosphatase for phosphatidylinositol-3,4,5-trisphosphate (PIP3) 1, 2. We have shown previously that PTEN negatively controls the G1/S cell cycle transition and regulates the levels of p27KIP1, a CDK inhibitor 3, 4. Recently, we and others have identified an ubiquitin E3 ligase, the SCFSKP2 complex, that mediates p27 ubiquitin-dependent proteolysis 5, 6, 7. Here we report that PTEN and the PI 3-kinase pathway regulate p27 protein stability. PTEN-deficiency in mouse embryonic stem (ES) cells causes a decrease of p27 levels with concomitant increase of SKP2, a key component of the SCFSKP2 complex. Conversely, in human glioblastoma cells, ectopic PTEN expression leads to p27 accumulation, which is accompanied by a reduction of SKP2. We found that ectopic expression of SKP2 alone is sufficient to reverse PTEN-induced p27 accumulation, restore the kinase activity of cyclin E/CDK2, and partially overcome the PTEN-induced G1 cell cycle arrest. Consistently, recombinant SCFSKP2 complex or SKP2 protein alone can rescue the defect in p27 ubiquitination in extracts prepared from cells treated with a PI 3-kinase inhibitor. Our findings suggest that SKP2 functions as a critical component in the PTEN/PI 3-kinase pathway for the regulation of p27KIP1 and cell proliferation.

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