PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway

PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway

^*Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520; and ^‡Howard Hughes Medical Institute and Department of Molecular and Medical Pharmacology, and Departments of ^¶Microbiology and Molecular Immunology, and ^‖Pathology and Laboratory Medicine, University of California, 650 Circle Drive South, Los Angeles, CA 90095-1735

Communicated by Harvey F. Lodish, Massachusetts Institute of Technology, Cambridge, MA (received for review October 26, 1998)

Abstract

To investigate the molecular basis of PTEN-mediated tumor suppression, we introduced a null mutation into the mouse Pten gene by homologous recombination in embryonic stem (ES) cells. Pten ^−/− ES cells exhibited an increased growth rate and proliferated even in the absence of serum. ES cells lacking PTEN function also displayed advanced entry into S phase. This accelerated G₁/S transition was accompanied by down-regulation of p27^KIP1, a major inhibitor for G₁ cyclin-dependent kinases. Inactivation of PTEN in ES cells and in embryonic fibroblasts resulted in elevated levels of phosphatidylinositol 3,4,5,-trisphosphate, a product of phosphatidylinositol 3 kinase. Consequently, PTEN deficiency led to dosage-dependent increases in phosphorylation and activation of Akt/protein kinase B, a well-characterized target of the phosphatidylinositol 3 kinase signaling pathway. Akt activation increased Bad phosphorylation and promoted Pten ^−/− cell survival. Our studies suggest that PTEN regulates the phosphatidylinositol 3,4,5,-trisphosphate and Akt signaling pathway and consequently modulates two critical cellular processes: cell cycle progression and cell survival.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: hong.sun{at}yale.edu or hwu{at}mednet.ucla.edu.
↵ § R.L. and D.-M.L. contributed equally to this work.
ABBREVIATIONS:

ES,

embryonic stem;

PIP,

phosphatidylinositol 4-phosphate;

PI3,

phosphatidylinositol 3;

PIP2,

phosphatidylinositol 4,5-bisphosphate;

PIP3,

phosphatidylinositol 3,4,5,-trisphosphate;

MEF,

mouse embryonic fibroblasts;

WT,

wild type;

CDK,

cyclin-dependent kinase;

PKB,

protein kinase B;

MAPK,

mitogen-activated protein kinase;

IGF-I,

insulin-like growth factor I;

TUNEL,

terminal deoxynucleotidyltransferase-mediated UTP end labeling;

FAK,

focal adhesion kinase