Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death.
Diphosphoinositol pentakisphosphate (InsP7) and bis-diphosphoinositol tetrakisphosphate contain pyrophosphate bonds. InsP7 is formed from inositol hexakisphosphate (InsP6) by a family of three inositol hexakisphosphate kinases (InsP6K). In this study we establish one of the InsP6Ks, InsP6K2, as a physiologic mediator of cell death. Overexpression of wild-type InsP6K2 augments the cytotoxic actions of multiple cell stressors in diverse cell lines, whereas transfection with a dominant negative InsP6K2 decreases cell death. During cell death, InsP6 kinase activity is enhanced, and intracellular InsP7 level is augmented. Deletion of InsP6K2 but not the other forms of InsP6K diminishes cell death, suggesting that InsP6K2 is the major InsP6 kinase involved in cell death. Cytotoxicity is associated with a translocation of InsP6K2 from nuclei to mitochondria, whereas the intracellular localization of the other isoforms of the enzyme does not change. The present study provides compelling evidence that endogenous InsP6K2, by generating InsP7, provides physiologic regulation of the apoptotic process.
Nagata
Eiichiro
E
Department of Neuroscience, Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Luo
Hongbo R
HR
Saiardi
Adolfo
A
Bae
Byoung-Il
BI
Suzuki
Norihiro
N
Snyder
Solomon H
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D007295:Inositol Phosphates; D034741:RNA, Small Interfering; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase; D019311:Staurosporine; D002945:Cisplatin