Inactivation of the inhibitory kappa B protein kinase nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis

Par-4 is a novel protein identified in cells undergoing apoptosis. The abil ity of Par-4 to promote apoptotic cell death is dependent on the binding an d inactivation of the atypical protein kinases C (PKCs). This subfamily of kinases has been reported to control nuclear factor kappa B (NF-kappa B) th rough the regulation of the I kappa B kinase activity. NF-kappa B activatio n by tumor necrosis factor alpha (TNF alpha) provides a survival signal tha t impairs the TNF alpha-induced apoptotic response. We show here that expre ssion of Par-4 inhibits the TNF alpha-induced nuclear translocation of p65 as well as the kappa B-dependent promoter activity. Interestingly, Par-4 ex pression blocks inhibitory kappa B protein (I kappa B) kinase activity, whi ch leads to the inhibition of I kappa B phosphorylation and degradation, in a manner that is dependent on its ability to inhibit lambda/iota PKC. Of p otential functional relevance, the expression of Par-4 allows TNF alpha to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par- 4 levels by oncogenic Ras sensitizes cells to TNF alpha-induced NF-kappa B activation.