Abstract
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 kappaB (NF-kappaB) through the regulation of the IkappaB kinase activity. NF-kappaB activation by tumor necrosis factor alpha (TNFalpha) provides a survival signal that impairs the TNFalpha-induced apoptotic response. We show here that expression of Par-4 inhibits the TNFalpha-induced nuclear translocation of p65 as well as the kappaB-dependent promoter activity. Interestingly, Par-4 expression blocks inhibitory kappaB protein (IkappaB) kinase activity, which leads to the inhibition of IkappaB phosphorylation and degradation, in a manner that is dependent on its ability to inhibit lambda/iotaPKC. Of potential functional relevance, the expression of Par-4 allows TNFalpha to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFalpha-induced NF-kappaB activation.
Highlights
The atypical protein kinase C (PKC)1 subfamily of isozymes has recently been the focus of considerable attention
The recent discovery that the product of par-4, a gene induced in cells undergoing apoptosis [26], binds to and inhibits the atypical subfamily of PKCs [3, 43], suggests that these kinases play important roles in the control of cell survival
The investigation of the mechanisms whereby the atypical PKCs regulate cell function is of potential great interest
Summary
The atypical protein kinase C (PKC) subfamily of isozymes (aPKCs) has recently been the focus of considerable attention. Upon cell stimulation by inflammatory cytokines such as TNF␣ or IL-1, which are potent activators of the atypical PKCs [17, 34, 35], IB␣ is phosphorylated in residues 32 and 36, which trigger the ubiquitination and subsequent degradation of IB through the proteosome pathway [33]. These events release NF-B, which translocates to the nucleus where it activates several genes involved in cell survival and inflammation (30 –33). Par-4 and NF-B Function potentiates TNF-induced apoptosis by inhibiting NF-B through the blockade of the aPKC-IKK signaling cascade
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