title: p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.
abstract: Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.
authors.affiliation: The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Koldobskiy
authors.forename: Anutosh
authors.initials: A
authors.lastname: Chakraborty
authors.forename: J Kent
authors.initials: JK
authors.lastname: Werner
authors.forename: Adele M
authors.initials: AM
authors.lastname: Snowman
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Juluri
authors.forename: M Scott
authors.initials: MS
authors.lastname: Vandiver
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.forename: Shira
authors.initials: S
authors.lastname: Heletz
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics; D004249:DNA Damage; D006801:Humans; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase