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J. Biol. Chem., Vol. 280, Issue 3, 2012-2019, January 21, 2005

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Phosphorylation-independent Stabilization of p27^kip1 by the Phosphoinositide 3-Kinase Pathway in Glioblastoma Cells^*

Christian H. Brandts, Benoit Bilanges, Gregor Hare, Frank McCormick, and David Stokoe

From the Cancer Research Institute, University of California, San Francisco, California 94115-0128

The PTEN tumor suppressor gene is a frequent target of somatic mutation, particularly in glioblastoma multiform and prostate cancer. The expression of PTEN in PTEN-mutant glioblastoma cells leads to a cell cycle arrest in G₀/G₁ that is mediated at least partially by increased p27^kip1 levels. Here we show that p27^kip1 is not regulated by transcriptional control but that p27^kip1 protein shows increased stability after inhibition of the phosphoinositide (PI) 3-kinase pathway. Because p27^kip1 protein stability is known to be regulated by phosphorylation, we have examined modifications in the phosphorylation pattern after PI 3-kinase inhibition. Biochemical evidence suggests that p27^kip1 is phosphorylated on several serine residues, including Ser-10 and Ser-178, but that phosphorylation is unaltered by PI 3-kinase activity. This is further confirmed by the inducible expression of p27^kip1 phosphorylation site mutants, suggesting that p27^kip1 is destabilized in a phosphorylation-independent manner by the PI 3-kinase pathway at the G₁/S transition.

Received for publication, July 23, 2004 , and in revised form, November 8, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Deutsche Forschungsgemeinschaft Grants Br1945/1-1 and Br1945/1-2. Present address: University of Muenster, Dept. of Medicine, Hematology and Oncology, Albert-Schweitzer-Str. 33, D-48149 Muenster, Germany.

Supported by National Institutes of Health Grants RO1CA79548 and P50CA97257 and the Concern Foundation. To whom correspondence should be addressed: Cancer Research Institute, University of California, 2340 Sutter St., San Francisco, CA 94115-0128. Tel.: 415-502-2598; Fax: 415-502-3179; E-mail: dstokoe{at}cc.ucsf.edu.

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