title: PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit.
abstract: 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-kappaB activity, it is controversial as to whether Akt activates NF-kappaB 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-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-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-kappaB-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-kappaB.
authors.affiliation: Department of Biochemistry, University of Virginia, Charlottesville, Virginia 22908, USA. mwm3y@virginia.edu
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.forename: Lee V
authors.initials: LV
authors.lastname: Madrid
authors.forename: Sandy D
authors.initials: SD
authors.lastname: Westerheide
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Yuan
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Young E
authors.initials: YE
authors.lastname: Whang
mesh_terms: D005786:Gene Expression Regulation / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D021381:Protein Transport; D014158:Transcription, Genetic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human