Increased levels of inositol hexakisphosphate (InsP6) protect HEK293 cells from tumor necrosis factor (alpha)- and Fas-induced apoptosis.
The overexpression of inositol 1,3,4-trisphosphate 5/6-kinase has recently been shown to protect HEK293 cells from tumor necrosis factor alpha (TNF(alpha))-induced apoptosis. This overexpression leads to an increase in the levels of both inositol 1,3,4,5,6-pentakisphosphate (InsP5) and inositol 1,2,3,4,5,6-hexakisphosphate (InsP6). Cells that overexpress InsP5 2-kinase have increased levels of InsP6 and are also protected from TNFalpha-induced apoptosis; furthermore, cells that express an RNA interference construct to the 2-kinase are deficient in InsP6 and are sensitized to TNFalpha-induced apoptosis. Therefore the protective effect of 5/6-kinase on TNFalpha-mediated apoptosis is due to an increase of InsP6 or to a metabolite derived from InsP6. Furthermore, we find that the InsP6 also protects from Fas-mediated apoptosis. No effect was seen in the endocytic rate of transferrin receptor, caspase 8 activity, or TNF receptor number at the cell surface. Cells that overexpress 2-kinase do show an increase in the amount of receptor-interacting protein (RIP), while cells with reduced InsP6 levels show relatively less RIP, providing a possible mechanism for the effect on apoptosis.
Verbsky
John
J
Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Majerus
Philip W
PW
D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D004705:Endocytosis; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007295:Inositol Phosphates / Q000737:chemistry; D010833:Phytic Acid / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D007295:Inositol Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C068271:inositol hexakisphosphate receptor; C013571:inositol pentaphosphate; D010833:Phytic Acid; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases