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Molecular and Cellular Biology, June 2002, p. 3842-3851, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3842-3851.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Essential Role of AKT-1/Protein Kinase B{alpha} in PTEN-Controlled Tumorigenesis

Bangyan Stiles,1 Valeriya Gilman,1,{dagger} Natalya Khanzenzon,1,{ddagger} Ralf Lesche,1,§ Annie Li,1 Rong Qiao,2 Xin Liu,2 and Hong Wu1*

Howard Hughes Medical Institute and Department of Molecular and Medical Pharmacology,1 Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California 90095-17352

Received 30 November 2001/ Returned for modification 8 January 2002/ Accepted 15 February 2002

PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP3) accumulation, enhanced entry into S phase, and better cell survival. Since PIP3 controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten-/- ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten-/- ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten-/- ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.

* Corresponding author. Mailing address: Howard Hughes Medical Institute and Department of Molecular and Medical Pharmacology, CHS23-234, UCLA School of Medicine, 650 Charles Young Dr. South, Los Angeles, CA 90095-1735. Phone: (310) 825-5160. Fax: (310) 267-0242. E-mail: hwu{at}mednet.ucla.edu.

{dagger} Present address: School of Dentistry, University of California at San Francisco, San Francisco, Calif.

{ddagger} Present address: Cedar-Sinai Medical Center, Los Angeles, CA 90048.

§ Present address: Epigenomics AG, 10435 Berlin, Germany.

Molecular and Cellular Biology, June 2002, p. 3842-3851, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3842-3851.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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