title: Inositol polyphosphate multikinase is a coactivator of p53-mediated transcription and cell death.
abstract: The tumor suppressor protein p53 is a critical stress response transcription factor that induces the expression of genes leading to cell cycle arrest, apoptosis, and tumor suppression. We found that mammalian inositol polyphosphate multikinase (IPMK) stimulated p53-mediated transcription by binding to p53 and enhancing its acetylation by the acetyltransferase p300 independently of its inositol phosphate and lipid kinase activities. Genetic or RNA interference (RNAi)-mediated knockdown of IPMK resulted in decreased activation of p53, decreased recruitment of p53 and p300 to target gene promoters, abrogated transcription of p53 target genes, and enhanced cell viability. Additionally, blocking the IPMK-p53 interaction decreased the extent of p53-mediated transcription. These results suggest that IPMK acts as a transcriptional coactivator for p53 and that it is an integral part of the p53 transcriptional complex facilitating cell death.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Risheng
authors.initials: R
authors.lastname: Xu
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.forename: Adele M
authors.initials: AM
authors.lastname: Snowman
authors.forename: Feng
authors.initials: F
authors.lastname: Rao
authors.forename: M Scott
authors.initials: MS
authors.lastname: Vandiver
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D005047:Etoposide; D017853:Phosphotransferases (Alcohol Group Acceptor); D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494826:BAX protein, human; C438378:BBC3 protein, human; C434257:inositol polyphosphate multikinase
references.citation: J Biol Chem. 2006 Dec 8;281(49):38109-16
references.pmid: 17050532
references.citation: J Biol Chem. 2008 Oct 10;283(41):27514-27524
references.pmid: 18694931
references.citation: Biotechniques. 2005 Nov;39(5):715-25
references.pmid: 16315372
references.citation: Cell. 2007 Jun 1;129(5):983-97
references.pmid: 17540177
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12783-8
references.pmid: 16123124
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1931-6
references.pmid: 12574499
references.citation: Toxicon. 2004 Sep 15;44(4):441-59
references.pmid: 15302526
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2306-11
references.pmid: 11226235
references.citation: FEBS Lett. 2000 Dec 15;486(3):300-4
references.pmid: 11119723
references.citation: Oncogene. 2007 Nov 22;26(53):7414-22
references.pmid: 17546051
references.citation: Mol Cell. 2001 Dec;8(6):1243-54
references.pmid: 11779500
references.citation: Cell. 2006 Mar 24;124(6):1169-81
references.pmid: 16564011
references.citation: Cancer. 1967 Mar;20(3):333-53
references.pmid: 4290058
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1911-4
references.pmid: 15665079
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14206-11
references.pmid: 12391334
references.citation: Mol Microbiol. 2003 Jul;49(2):457-68
references.pmid: 12828642
references.citation: Nature. 2012 Jan 09;481(7381):335-40
references.pmid: 22230954
references.citation: Cell. 2008 May 16;133(4):612-26
references.pmid: 18485870
references.citation: Nature. 2005 Aug 4;436(7051):725-30
references.pmid: 16079851
references.citation: Cell Metab. 2011 Feb 2;13(2):215-21
references.pmid: 21284988
references.citation: Cell. 2003 Sep 5;114(5):559-72
references.pmid: 13678580
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1391-6
references.pmid: 21220345
references.citation: J Biol Chem. 2012 Oct 12;287(42):35360-35369
references.pmid: 22896696
references.citation: Science. 2000 Mar 17;287(5460):2026-9
references.pmid: 10720331
references.citation: Eur J Biochem. 1970 Jan;12(1):31-9
references.pmid: 5434281
references.citation: Cell. 1993 Aug 27;74(4):609-19
references.pmid: 8358790
references.citation: Cell Signal. 2007 Jul;19(7):1497-504
references.pmid: 17355905
references.citation: Nat Rev Cancer. 2003 May;3(5):330-8
references.pmid: 12724731
references.citation: Eur J Cancer. 1998 Sep;34(10):1514-21
references.pmid: 9893622
references.citation: Nat Cell Biol. 2010 Apr;12(4):380-9
references.pmid: 20228809
references.citation: Mol Cell Biol. 1993 Apr;13(4):2586-92
references.pmid: 8455631
references.citation: Nature. 2005 Aug 4;436(7051):642
references.pmid: 16079833
references.citation: Neuron. 2005 Jul 7;47(1):29-41
references.pmid: 15996546
references.citation: J Biol Chem. 2012 Nov 2;287(45):38347-55
references.pmid: 22992733
references.citation: Cell. 1993 Nov 19;75(4):817-25
references.pmid: 8242752
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20947-51
references.pmid: 21078964
references.citation: Science. 2003 Jan 3;299(5603):112-4
references.pmid: 12434013
references.citation: Nat Rev Cancer. 2013 Feb;13(2):83-96
references.pmid: 23303139
references.citation: Oncogene. 2009 Jun 25;28(25):2383-92
references.pmid: 19430495
references.citation: Oncogene. 2002 Mar 14;21(12):1882-9
references.pmid: 11896621
references.citation: Mol Cell. 2001 Mar;7(3):683-94
references.pmid: 11463392
references.citation: Cell. 1997 Aug 22;90(4):595-606
references.pmid: 9288740
references.citation: Mol Gen Genet. 1994 May 10;243(3):315-24
references.pmid: 8043104
references.citation: Nat Med. 2003 Mar;9(3):338-42
references.pmid: 12563316
references.citation: Cell. 1995 Jan 27;80(2):293-9
references.pmid: 7834749
references.citation: Nat Immunol. 2011 Jun 19;12(8):752-60
references.pmid: 21685907
references.citation: Science. 2003 Jan 3;299(5603):114-6
references.pmid: 12434012
references.citation: Microbiol Mol Biol Rev. 2008 Mar;72(1):197-210, table of contents
references.pmid: 18322039
references.citation: Cell. 2006 Dec 29;127(7):1323-34
references.pmid: 17182091
references.citation: J Biol Chem. 2001 Jul 6;276(27):24965-70
references.pmid: 11337497
references.citation: Curr Biol. 1999 Nov 18;9(22):1323-6
references.pmid: 10574768
references.citation: Nature. 1996 Sep 12;383(6596):166-8
references.pmid: 8774880
references.citation: Mol Cell Biol. 1999 Feb;19(2):1202-9
references.pmid: 9891054
references.citation: Nat Rev Cancer. 2002 Aug;2(8):594-604
references.pmid: 12154352
references.citation: Cell. 2010 Dec 10;143(6):897-910
references.pmid: 21145457
references.citation: Sci Signal. 2012 Jun 19;5(229):ra44
references.pmid: 22715467
references.citation: Biochem J. 2002 Sep 1;366(Pt 2):549-56
references.pmid: 12027805