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Membrane lipid regulation of the tumor suppressor phosphatase PTEN
Author(s) -
Goswami R.,
Singh D.,
Phillips G.,
Kilkus J.,
Dawson G.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.38_4.x
Subject(s) - pten , ceramide , staurosporine , tensin , biology , protein kinase b , phosphatase , microbiology and biotechnology , cancer research , pi3k/akt/mtor pathway , signal transduction , apoptosis , protein kinase c , phosphorylation , biochemistry
The neutral sphingolipid ceramide has been implicated in the apoptotic death of cells by a number of different mechanisms and we now present evidence that one of its actions is to activate the tumor supressor protein PTEN (phosphatase and tensin homolog deleted from chromosome 10). PTEN is mutated in multiple advanced cancers, is absent from many tumor cells such as gliomas, and functions largely as a polyphosphoinositide phosphatase. PTEN with a red‐fluorescent protein (RFP) tag was overexpressed in both a human cell line derived from oligodendroglioma (HOG) and a rat pheochromocytoma cells line (PC12) by means of an inducible promoter system (tet‐OFF). Induction of the gene by removal of doxocycline showed a generalized (cytosolic) distribution of PTEN which was changed to a more membrane‐associated pattern following treatment with C2‐ceramide. Activation of the cell death pathway with either staurosporine, wortmannin or C2‐ceramide was facilitated by PTEN expression while lowering PTEN expression with antisense constructs partially blocked cell death. The staurosporine‐induced increase in ceramide was localized to the Raft (detergent‐resistant‐membrane fraction) where active PTEN is also found. We propose that formation of ceramide during apoptosis results in the translocation of PTEN to the plasma membrane, where it can hydrolyze the polyphosphoinositides which normally activate the key antiapoptotic protein, phospho‐Akt (protein kinase B). Since ceramide may also activate a Phospho‐Akt phosphatase, this may further explain the high pro‐apoptoic potential of ceramide.