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Cancer Research 68, 1723, March 15, 2008. doi: 10.1158/0008-5472.CAN-07-1963
© 2008 American Association for Cancer Research

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Cell, Tumor, and Stem Cell Biology

PTEN Has Tumor-Promoting Properties in the Setting of Gain-of-Function p53 Mutations

Yunqing Li1, Fadila Guessous1, Sherwin Kwon5, Manish Kumar5, Opeyemi Ibidapo1, Lauren Fuller1, Elizabeth Johnson1, Bachchu Lal4,5, Isa Hussaini3, Yongde Bao2, John Laterra4,5, David Schiff1 and Roger Abounader1,2

Departments of 1 Neurology, 2 Microbiology, and 3 Pathology, University of Virginia, Charlottesville, Virginia and 4 Department of Neurology and 5 Kennedy Krieger Research Institute, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Roger Abounader, University of Virginia Health System, P. O. Box 800168, Charlottesville, VA 22908. Phone: 434-982-6634; Fax: 434-243-6843; E-mail: ra6u{at}virginia.edu.

Key Words: PTEN • p53 • gain-of-function mutations • tumor suppressor • oncogene

We show, for the first time, that the tumor suppressor PTEN can have tumor-promoting properties. We show that PTEN acquires these unexpected properties by enhancing gain-of-function mutant p53 (mut-p53) protein levels. We find that PTEN restoration to cells harboring mut-p53 leads to induction of G1-S cell cycle progression and cell proliferation and to inhibition of cell death. Conversely, PTEN inhibition in cells expressing wild-type PTEN and mut-p53 leads to inhibition of cell proliferation and inhibition of in vivo tumor growth. We show the dependency of the tumor-promoting effects of PTEN on mut-p53 by showing that knockdown of mut-p53 expression inhibits or reverses the tumor-promoting effects of PTEN. Mechanistically, we show that PTEN expression enhances mut-p53 protein levels via inhibition of mut-p53 degradation by Mdm2 and possibly also via direct protein binding. These findings describe a novel function of PTEN and have important implications for experimental and therapeutic strategies that aim at manipulating PTEN or p53 in human tumors. They suggest that the mutational status of PTEN and p53 should be considered to achieve favorable therapeutic outcomes. The findings also provide an explanation for the low frequency of simultaneous mutations of PTEN and p53 in human cancer. [Cancer Res 2008;68(6):1723–31]




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2008 by the American Association for Cancer Research.