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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-κB transcription of anti-apoptotic factors. We now report a link between the TNF-R1 and inositol phosphate signaling pathways. We observed that overexpression of iuositol 1,3,4-trisphosphate 5/6-kinase (5/6-kinase) inhibited apoptosis induced by TNFα. The antiapoptotic effect by 5/6-kinase is not attributable to NF-B activation, as no changes were detected in the levels of NF-κB DNA binding, IκBα degradation, or antiapoptotic factors, such as x-linked inhibitor of apoptosis protein. Decreased expression of 5/6-kinase by RNA interference rendered HeLa cells more susceptible to TNFα-induced apoptosis. Overexpression of 5/6-kinase in human embryonic kidney 293 cells inhibited TNFαinduced activation of caspases-8, -3, and -9, BID, and poly(ADP-ribose) polymerase. However, 5/6-kinase did not protect against Fas-, etoposide-, or cycloheximideinduced 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 TNFα-induced apoptosis by interfering with the activation of TNF-R1-associated death domain. [ABSTRACT FROM AUTHOR]