Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells.
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 G(0)/G(1) 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 G(1)/S transition.
Brandts
Christian H
CH
Cancer Research Institute, University of California, San Francisco, California 94115-0128, USA.
Bilanges
Benoit
B
Hare
Gregor
G
McCormick
Frank
F
Stokoe
David
D
D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D010766:Phosphorylation; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology
D018797:Cell Cycle Proteins; D002867:Chromones; D017931:DNA Primers; D009025:Morpholines; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human