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

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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 κB (NF-κB) through the regulation of the IκB kinase activity. NF-κB activation by tumor necrosis factor α (TNFα) provides a survival signal that impairs the TNFα-induced apoptotic response. We show here that expression of Par-4 inhibits the TNFα-induced nuclear translocation of p65 as well as the κB-dependent promoter activity. Interestingly, Par-4 expression blocks inhibitory κB protein (IκB) kinase activity, which leads to the inhibition of IκB phosphorylation and degradation, in a manner that is dependent on its ability to inhibit λ/ιPKC. Of potential functional relevance, the expression of Par-4 allows TNFα to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFα-induced NF-κB activation.

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This work was supported by Grants SAF96-0216 from CICYT, PM96-0002-C02 from DGICYT, and BIO4-CT97-2071 from the European Union, and by funds from Glaxo Wellcome Spain, and has benefited of an institutional grant from Fundación Ramón Areces to the CBM.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.

These authors have contributed equally to this work and should be considered as first authors.