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Papers In Press, published online ahead of print January 17, 2002
Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908
Corresponding Author: mwm3y{at}virginia.edu
PTEN is a lipid phosphatase responsible for downregulating the phosphoinositide 3-kinase (PI3K) product phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 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, IkB alpha 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 (CREB) 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 PI3K, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, since 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.
J. Biol. Chem, 10.1074/jbc.M108670200
Submitted on September 7, 2001
Revised on January 17, 2002
Accepted on January 16, 2002
PTEN blocks TNF-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit
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