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Originally published In Press as doi:10.1074/jbc.M108670200 on January 17, 2002

J. Biol. Chem., Vol. 277, Issue 13, 11116-11125, March 29, 2002
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PTEN Blocks Tumor Necrosis Factor-induced NF-kappa B-dependent Transcription by Inhibiting the Transactivation Potential of the p65 Subunit*

Marty W. MayoDagger §, Lee V. Madrid||**, Sandy D. Westerheide||, David R. Jones§, Xiu-Juan Yuan||, Albert S. Baldwin Jr.||**Dagger Dagger , and Young E. Whang||§§

From the Dagger  Department of Biochemistry and Molecular Genetics and the § Department of Surgery, the University of Virginia, Charlottesville, Virginia 22908 and the || Lineberger Comprehensive Cancer Center, ** Curriculum in Genetics and Molecular Biology, the Dagger Dagger  Department of Biology and the §§ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappa B activity, it is controversial as to whether Akt activates NF-kappa B predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappa B. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappa B transcriptional activity. PTEN failed to block TNF-induced IKK activation, Ikappa Balpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappa B. However, PTEN inhibited NF-kappa B-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappa B-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappa B.

* This work was supported by National Institutes of Health Grants CA78595 (to M. W. M.), CA72771 (to A. S. B.), CA85772 (to Y. E. W.), CA83920 (to D. R. J.), and CA75080 (to A. S. B. and M. W. M.), by the University of Virginia Paul Mellon Prostate Cancer Research Institute (to M. W. M.), and by the United States Army Prostate Cancer Research Program Grant DAMD17-00-1-0037 (to Y. E. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Genetics, Box 800733, University of Virginia, Charlottesville, VA 22908. Tel.: 434-924-2509; Fax: 434-924-5069; E-mail: mwm3y@virginia.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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