Inositol 1,3,4-trisphosphate 5/6-kinase inhibits tumor necrosis factor-induced apoptosis

Tumor necrosis factor receptor 1 (TNF-R1) signaling elicits a wide range of biological responses, including inflammation, proliferation, differentiation, and Apoptosis. TNF-R1 activates both caspase-mediated Apoptosis and NF-kappaB transcription of anti-apoptotic factors. We now report a link between the TNF-R1 and inositol phosphate signaling pathways. We observed that overexpression of inositol 1,3,4-trisphosphate 5/6-kinase (5/6-kinase) inhibited Apoptosis induced by TNFalpha. The anti-apoptotic effect by 5/6-kinase is not attributable to NF-kappaB activation, as no changes were detected in the levels of NF-kappaB DNA binding, IkappaBalpha degradation, or anti-apoptotic factors, such as x-linked inhibitor of Apoptosis protein. Decreased expression of 5/6-kinase by RNA interference rendered HeLa cells more susceptible to TNFalpha-induced Apoptosis. Overexpression of 5/6-kinase in human embryonic kidney 293 cells inhibited TNFalpha-induced activation of caspases-8, -3, and -9, BID, and poly(ADP-ribose) polymerase. However, 5/6-kinase did not protect against Fas-, etoposide-, or cycloheximide-induced Apoptosis. Further, 5/6-kinase protected against Apoptosis induced by the overexpression of TNF-R1-associated death domain but not Fas-associated death domain. Therefore, we suggest that 5/6-kinase modifies TNFalpha-induced Apoptosis by interfering with the activation of TNF-R1-associated death domain.