Current Biology
Volume 8, Issue 21, 22 October 1998, Pages 1195-1198, S1
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Brief Communications
Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC

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Abstract

Glioblastomas are highly malignant tumors of the central nervous system that are resistant to radiation and chemotherapy [1]. We explored the role of the phosphatidylinositol (PI) 3-kinase signal transduction pathway in glioblastomas, as this pathway has been shown to inhibit apoptosis induced by cytokine withdrawal and the detachment of cells from the extracellular matrix [2]. Components of this pathway have been implicated in tumor development [3], [4], [5], [6]. We show that glioblastoma cells, in contrast to primary human astrocytes, contain high endogenous protein kinase B (PKB/Akt) activity and high levels of PI 3,4,5-triphosphate (PI(3,4,5)P3) and PI(3,4)P2, the lipid products of PI 3-kinase. These glioblastoma cells express mutant forms of the putative 3′ phospholipid phosphatase PTEN, also known as MMAC. Expression of wild-type PTEN derived from primary astrocytes, but not of mutant forms of PTEN, reduced the levels of 3′ phosphoinositides and inhibited PKB/Akt activity. PTEN antagonized the activation of PKB/Akt by growth factors, by activated PI 3-kinase and by PI-dependent protein kinase-1 (PDK1), but did not antagonize the phospholipid-independent activation of PKB/Akt lacking the pleckstrin homology (PH) domain. These results suggest a role for PTEN in regulating the activity of the PI 3-kinase pathway in malignant human cells.

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D Haas-Kogan, N Shalev and G Yount, Department of Radiation Oncology, University of California, San Francisco, California 94115, USA.

M Wong and D Stokoe, Cancer Research Institute, University of California, San Francisco, California 94115, USA.

G Mills, The University of Texas MD Anderson Cancer Center, Texas 77030, USA.

E-mail address for D Haas-Kogan (corresponding author): [email protected].

E-mail address for D Stokoe (corresponding author): [email protected].