title: The RNA helicase p68 modulates expression and function of the Δ133 isoform(s) of p53, and is inversely associated with Δ133p53 expression in breast cancer.
abstract: The RNA helicase p68 is a potent co-activator of p53-dependent transcription in response to DNA damage. Previous independent studies have indicated that p68 and the Δ133p53 isoforms, which modulate the function of full-length p53, are aberrantly expressed in breast cancers. Here we identify a striking inverse association of p68 and Δ133p53 expression in primary breast cancers. Consistent with these findings, small interfering RNA depletion of p68 in cell lines results in a p53-dependant increase of Δ133p53 in response to DNA damage, suggesting that increased Δ133p53 expression could result from downregulation of p68 and provide a potential mechanistic explanation for our observations in breast cancer. Δ133p53α, which has been shown to negatively regulate the function of full-length p53, reciprocally inhibits the ability of p68 to stimulate p53-dependent transcription from the p21 promoter, suggesting that Δ133p53α may be competing with p68 to regulate p53 function. This hypothesis is underscored by our observations that p68 interacts with the C-terminal domain of p53, co-immunoprecipitates 133p53α from cell extracts and interacts only with p53 molecules that are able to form tetramers. These data suggest that p68, p53 and 133p53α may form part of a complex feedback mechanism to regulate the expression of Δ133p53, with consequent modification of p53-mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53.
authors.affiliation: Centre for Oncology & Molecular Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, Tayside, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Moore
authors.forename: L B
authors.initials: LB
authors.lastname: Jordan
authors.forename: S E
authors.initials: SE
authors.lastname: Bray
authors.forename: L
authors.initials: L
authors.lastname: Baker
authors.forename: P R
authors.initials: PR
authors.lastname: Quinlan
authors.forename: C A
authors.initials: CA
authors.lastname: Purdie
authors.forename: A M
authors.initials: AM
authors.lastname: Thompson
authors.forename: J-C
authors.initials: JC
authors.lastname: Bourdon
authors.forename: F V
authors.initials: FV
authors.lastname: Fuller-Pace
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D053487:DEAD-box RNA Helicases
references.citation: Mol Cell Biol. 2003 Apr;23(8):2927-41
references.pmid: 12665590
references.citation: J Pathol. 1998 Apr;184(4):351-9
references.pmid: 9664900
references.citation: EMBO J. 2005 Feb 9;24(3):543-53
references.pmid: 15660129
references.citation: Oncogene. 2002 Oct 3;21(44):6722-8
references.pmid: 12360399
references.citation: EMBO J. 2001 Mar 15;20(6):1341-52
references.pmid: 11250900
references.citation: J Cell Biochem. 2008 Apr 1;103(5):1438-51
references.pmid: 17960593
references.citation: J Biol Chem. 2007 Nov 9;282(45):32773-9
references.pmid: 17724023
references.citation: Cell Death Differ. 2006 Jun;13(6):962-72
references.pmid: 16601753
references.citation: Nat Cell Biol. 2009 Sep;11(9):1135-42
references.pmid: 19701195
references.citation: Mol Cell Biol. 1999 Aug;19(8):5363-72
references.pmid: 10409727
references.citation: Nat Rev Cancer. 2002 Aug;2(8):594-604
references.pmid: 12154352
references.citation: EMBO J. 1998 May 15;17(10):2748-58
references.pmid: 9582268
references.citation: Hum Mutat. 2002 Jun;19(6):607-14
references.pmid: 12007217
references.citation: Oncogene. 2008 Apr 24;27(19):2661-72
references.pmid: 18026140
references.citation: Mol Cell. 1999 Feb;3(2):181-93
references.pmid: 10078201
references.citation: Nat Cell Biol. 2007 May;9(5):604-11
references.pmid: 17435748
references.citation: Dev Cell. 2006 Oct;11(4):547-60
references.pmid: 17011493
references.citation: Cell Cycle. 2007 May 15;6(10):1172-6
references.pmid: 17495528
references.citation: BMC Mol Biol. 2004 Aug 06;5:11
references.pmid: 15298701
references.citation: Cell Cycle. 2009 Apr 15;8(8):1238-48
references.pmid: 19305147
references.citation: Oncogene. 2003 Jan 9;22(1):151-6
references.pmid: 12527917
references.citation: Oncogene. 2001 Nov 22;20(53):7734-43
references.pmid: 11753651
references.citation: Genes Dev. 2009 Feb 1;23(3):278-90
references.pmid: 19204115
references.citation: Eur J Cancer. 2007 Feb;43(3):617-23
references.pmid: 17215121
references.citation: Clin Cancer Res. 2006 Feb 15;12(4):1157-67
references.pmid: 16489069
references.citation: Science. 1998 Nov 20;282(5393):1497-501
references.pmid: 9822382
references.citation: J Clin Pathol. 1995 Sep;48(9):876-8
references.pmid: 7490328
references.citation: Pathobiology. 2008;75(2):132-9
references.pmid: 18544968
references.citation: Mol Cell Biol. 2002 Aug;22(15):5443-50
references.pmid: 12101238
references.citation: Curr Mol Med. 2008 Dec;8(8):845-9
references.pmid: 19075680
references.citation: Oncogene. 2005 Apr 18;24(17):2899-908
references.pmid: 15838523
references.citation: Curr Opin Genet Dev. 2009 Feb;19(1):18-24
references.pmid: 19179064
references.citation: Nat Cell Biol. 2002 Jun;4(6):462-7
references.pmid: 12032546
references.citation: Clin Cancer Res. 2008 Mar 15;14(6):1659-68
references.pmid: 18310316
references.citation: Science. 2008 Mar 7;319(5868):1352-5
references.pmid: 18323444
references.citation: Mol Cell Biol. 2001 Nov;21(21):7366-79
references.pmid: 11585918
references.citation: Cancer Res. 2008 Oct 1;68(19):7938-46
references.pmid: 18829551
references.citation: Oncogene. 2007 Apr 2;26(15):2157-65
references.pmid: 17401424
references.citation: Cell. 1993 Nov 19;75(4):817-25
references.pmid: 8242752
references.citation: Oncogene. 2010 May 6;29(18):2691-700
references.pmid: 20190805
references.citation: Genes Dev. 2005 Sep 15;19(18):2122-37
references.pmid: 16131611
references.citation: Nature. 2000 Nov 16;408(6810):307-10
references.pmid: 11099028
references.citation: Oncogene. 2007 May 17;26(23):3329-37
references.pmid: 17130833
references.citation: Nucleic Acids Res. 2006;34(15):4206-15
references.pmid: 16935882
references.citation: Mol Cancer Res. 2005 Jun;3(6):355-63
references.pmid: 15972854