title: A hidden role of the inactivated FANCD2: upregulating ΔNp63.
abstract: A compromised Fanconi Anemia (FA) signaling pathway, often resulting from an inactivated FANCD2, was recently recognized to contribute to the development of non-FA human tumors. However, it is largely unknown as to how an impaired FA pathway or an inactivated FANCD2 promotes tumorigenesis. Here we unexpectedly found that ΔNp63 mRNA was expressed at high levels in human cancer cells carrying an impaired FA pathway compared to the corresponding control cells carrying an intact FA pathway. This observation was recapitulated upon conditionally managing the status of FANCD2 monoubiquitination /activation in 293T cells. Importantly, ΔNp63 elevation upon FANCD2 inactivation was confirmed in human fibroblasts derived from FA patients. Moreover, we have identified a 189 bp DNA fragment downstream of the ΔNp63 promoter (P2) that can mediate the upregulation of ΔNp63 by an inactivated FANCD2, and determined that elevated ΔNp63 is high enough to promote cancer cell proliferation and metastasis. In vivo, the elevation of FAVL, a tumor promotion factor that inhibits FANCD2 activation, was found to be positively associated with ΔNp63 expression in human cancer tissues. Collectively, these results document a novel role of an inactivated FANCD2 in upregulating ΔNp63, advancing our understanding of how an impaired FA pathway contributes to the pathogenesis of human cancer.
authors: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, USA.
authors: Jayabal
authors: J
authors: Panneerselvam
authors: Anna
authors: A
authors: Pickering
authors: Jun
authors: J
authors: Zhang
authors: Hong
authors: H
authors: Wang
authors: Hui
authors: H
authors: Tian
authors: Junnian
authors: J
authors: Zheng
authors: Peiwen
authors: P
authors: Fei
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
references: Oncogene. 2007 Aug 9;26(36):5169-83
references: 17334395
references: Nature. 2000 Mar 2;404(6773):99-103
references: 10716451
references: Cell Cycle. 2012 Jun 15;11(12):2367-79
references: 22672905
references: Nature. 2002 Apr 4;416(6880):560-4
references: 11932750
references: Cell Cycle. 2012 Dec 15;11(24):4545-51
references: 23165243
references: Oncotarget. 2013 Feb;4(2):329-45
references: 23593654
references: Oncogene. 2013 Mar 14;32(11):1460-8
references: 22543586
references: Cell Cycle. 2010 Jun 15;9(12):2434-41
references: 20519941
references: Cell Cycle. 2013 May 1;12(9):1331-2
references: 23588071
references: Cell Cycle. 2013 Mar 1;12(5):713-4
references: 23422862
references: Oncotarget. 2012 Jan;3(1):5-6
references: 22403740
references: Cell Cycle. 2012 Aug 15;11(16):3036-44
references: 22871734
references: Semin Hematol. 2006 Jul;43(3):147-56
references: 16822457
references: Oncogene. 2013 Oct;32(40):4758-65
references: 23128396
references: Oncotarget. 2013 Feb;4(2):256-68
references: 23530091
references: Curr Opin Hematol. 2003 Jan;10(1):68-76
references: 12483114
references: Oncogene. 2011 Dec 1;30(48):4802-13
references: 21602882
references: Nat Med. 2003 May;9(5):568-74
references: 12692539
references: Cancer Biol Ther. 2006 Dec;5(12):1632-6
references: 17106252
references: Blood. 2006 Jun 1;107(11):4223-33
references: 16493006
references: Cancer Cell. 2006 Jan;9(1):45-56
references: 16413471
references: Oncotarget. 2013 Jun;4(6):923-35
references: 23798621
references: Nat Rev Genet. 2007 Oct;8(10):735-48
references: 17768402
references: Cell Cycle. 2012 Aug 1;11(15):2947-55
references: 22828653
references: Oncotarget. 2012 Mar;3(3):299-313
references: 22431556
references: Oncotarget. 2012 Dec;3(12):1615-28
references: 23271044
references: Cell Cycle. 2008 Feb 1;7(3):407-13
references: 18277096
references: Oncotarget. 2013 Feb;4(2):192-205
references: 23545251
references: Nat Genet. 2003 Oct;35(2):165-70
references: 12973351
references: Cell Cycle. 2013 Mar 1;12(5):803-9
references: 23388460
references: Oncogene. 2012 Oct 4;31(40):4362-71
references: 22249251
references: Oncotarget. 2013 Apr;4(4):622-35
references: 23599172
references: Cell Cycle. 2011 Aug 1;10(15):2574-82
references: 21734451
references: PLoS One. 2010 Oct 13;5(10):e13313
references: 20967207
references: J Clin Invest. 2010 May;120(5):1524-34
references: 20407210
references: Nature. 1999 Apr 22;398(6729):714-8
references: 10227294
references: J Clin Invest. 2007 May;117(5):1370-80
references: 17446929
references: Oncotarget. 2013 May;4(5):705-14
references: 23670029
references: Oncotarget. 2012 Oct;3(10):1068-111
references: 23085539
references: Oncotarget. 2013 Feb;4(2):289-97
references: 23470527
references: Cell Cycle. 2005 Jan;4(1):80-6
references: 15611632
references: Cell Cycle. 2007 Feb 1;6(3):300-4
references: 17264676
references: Cell Cycle. 2012 Nov 1;11(21):3983-96
references: 22987153
references: Nucleic Acids Res. 2009 Oct;37(18):6092-104
references: 19700772