Inactivation of the Inhibitory κB Protein Kinase/Nuclear Factor κB Pathway by Par-4 Expression Potentiates Tumor Necrosis Factor α-induced Apoptosis

Par-4 is a novel protein identified in cells undergoing apoptosis. The ability of Par-4 to promote apoptotic cell death is dependent on the binding and inactivation of the atypical protein kinases C (PKCs). This subfamily of kinases has been reported to control nuclear factor Kappa B (NF- Kappa B) through the regulation of the I Kappa B kinase activity. NF- Kappa B activation by tumor necrosis factor alpha (TNF alpha ) provides a survival signal that impairs the TNF alpha -induced apoptotic response. We show here that expression of Par-4 inhibits the TNF alpha -induced nuclear translocation of p65 as well as the Kappa B-dependent promoter activity. Interestingly, Par-4 expression blocks inhibitory Kappa B protein (I Kappa B) kinase activity which 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 potential 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.