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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / genetics*
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Cell Cycle / genetics
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Cell Line, Tumor
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Colonic Neoplasms / pathology*
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Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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DNA Damage
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Humans
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Phosphotransferases (Phosphate Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Phosphate Group Acceptor) / genetics
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Phosphotransferases (Phosphate Group Acceptor) / metabolism
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Phosphotransferases (Phosphate Group Acceptor) / physiology*
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Protein Binding
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
Substances
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Cyclin-Dependent Kinase Inhibitor p21
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Tumor Suppressor Protein p53
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Phosphotransferases (Phosphate Group Acceptor)
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inositol hexakisphosphate kinase