title: GFI1 is repressed by p53 and inhibits DNA damage-induced apoptosis.
abstract: GFI1 is a transcriptional repressor that plays a critical role in hematopoiesis and has also been implicated in lymphomagenesis. It is still poorly understood how GFI1 expression is regulated in the hematopoietic system. We show here that GFI1 transcription was repressed by the tumor suppressor p53 in hematopoietic cells. Knockdown of p53 resulted in increased GFI1 expression and abolished DNA damage-induced GFI1 downregulation. In contrast, GFI1 expression was reduced and its downregulation in response to DNA damage was rescued upon restoration of p53 function in p53-deficient cells. In luciferase reporter assays, wild type p53, but not a DNA binding-defective p53 mutant, repressed the GFI1 promoter. Chromatin immunoprecipitation (ChIP) assays demonstrated that p53 bound to the proximal region of the GFI1 promoter. Detailed mapping of the GFI1 promoter indicated that GFI1 core promoter region spanning from -33 to +6 bp is sufficient for p53-mediated repression. This core promoter region contains a putative p53 repressive response element, mutation of which abolished p53 binding to and repression of GFI1 promoter. Significantly, apoptosis induced by DNA damage was inhibited upon Gfi1 overexpression, but augmented following GFI1 knockdown. Our data establish for the first time that GFI1 is repressed by p53 and add to our understanding of the roles of GFI1 in normal hematopoiesis and lymphomagenesis.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Pei
authors.initials: P
authors.lastname: Du
authors.forename: Fangqiang
authors.initials: F
authors.lastname: Tang
authors.forename: Yaling
authors.initials: Y
authors.lastname: Qiu
authors.forename: Fan
authors.initials: F
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051379:Mice; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D004247:DNA
references.citation: Oncogene. 1996 Apr 18;12(8):1789-801
references.pmid: 8622900
references.citation: Cancer Res. 2011 Apr 1;71(7):2781-92
references.pmid: 21447739
references.citation: Mol Cell Biol. 1993 Dec;13(12):7774-81
references.pmid: 8246993
references.citation: Nature. 2004 Oct 21;431(7011):1002-7
references.pmid: 15457180
references.citation: EMBO J. 2004 Oct 13;23(20):4116-25
references.pmid: 15385956
references.citation: Mol Cell Biol. 1993 Mar;13(3):1759-68
references.pmid: 8441411
references.citation: Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a000935
references.pmid: 20679336
references.citation: Oncogene. 2010 Apr 1;29(13):1963-75
references.pmid: 20062079
references.citation: Eur J Immunol. 2007 Dec;37(12):3551-63
references.pmid: 18034420
references.citation: J Biol Chem. 2007 Mar 2;282(9):6473-83
references.pmid: 17197705
references.citation: Nat Rev Cancer. 2009 Oct;9(10):724-37
references.pmid: 19776742
references.citation: Immunity. 2002 May;16(5):733-44
references.pmid: 12049724
references.citation: Br J Haematol. 2009 Aug;146(3):257-69
references.pmid: 19500100
references.citation: Nature. 2006 Sep 14;443(7108):214-7
references.pmid: 16957739
references.citation: Prostate. 2010 Mar 1;70(4):377-89
references.pmid: 19866464
references.citation: Cancer Res. 1995 Nov 15;55(22):5187-90
references.pmid: 7585571
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14569-73
references.pmid: 8962093
references.citation: Exp Hematol. 2002 Jul;30(7):729-37
references.pmid: 12135670
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D523-7
references.pmid: 14681473
references.citation: Cancer Cell. 2003 Nov;4(5):371-81
references.pmid: 14667504
references.citation: Trends Cell Biol. 2011 Jun;21(6):344-53
references.pmid: 21601459
references.citation: Science. 1998 Nov 20;282(5393):1497-501
references.pmid: 9822382
references.citation: Cell Stem Cell. 2009 Jan 9;4(1):37-48
references.pmid: 19128791
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1433-8
references.pmid: 19164764
references.citation: Cell Cycle. 2010 Mar 1;9(5):870-9
references.pmid: 20160511
references.citation: Mol Ther. 2006 Feb;13(2):382-90
references.pmid: 16275162
references.citation: Cancer Res. 2004 Jul 1;64(13):4419-27
references.pmid: 15231650
references.citation: Exp Hematol. 2003 May;31(5):372-81
references.pmid: 12763135
references.citation: Oncogene. 2010 May 13;29(19):2843-52
references.pmid: 20190815
references.citation: Oncogene. 2007 May 24;26(24):3541-50
references.pmid: 17213822
references.citation: Leukemia. 2012 Jul;26(7):1555-63
references.pmid: 22285998
references.citation: Cell. 2008 May 16;133(4):727-41
references.pmid: 18485879
references.citation: J Virol. 2009 Aug;83(16):8051-61
references.pmid: 19474094
references.citation: Cold Spring Harb Perspect Biol. 2010 Jan;2(1):a001008
references.pmid: 20182602
references.citation: Mol Cell Biol. 2005 Sep;25(17):7423-31
references.pmid: 16107691
references.citation: Cancer Cell. 2013 Feb 11;23(2):200-14
references.pmid: 23410974
references.citation: Crit Rev Oncol Hematol. 2006 Aug;59(2):85-97
references.pmid: 16716599
references.citation: Nucleic Acids Res. 1996 Jul 1;24(13):2528-34
references.pmid: 8692692
references.citation: Cancer Res. 2004 Oct 1;64(19):6874-82
references.pmid: 15466176
references.citation: Stem Cells. 2011 Feb;29(2):376-85
references.pmid: 21732494
references.citation: Cell Death Differ. 2006 Jun;13(6):951-61
references.pmid: 16575405
references.citation: Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a001883
references.pmid: 20066118
references.citation: Oncogene. 1998 Nov 19;17(20):2661-7
references.pmid: 9840930
references.citation: Blood. 2009 May 28;113(22):5466-75
references.pmid: 19346496
references.citation: Blood. 2012 Apr 19;119(16):3668-83
references.pmid: 22275381
references.citation: J Virol. 1997 Jan;71(1):9-16
references.pmid: 8985317
references.citation: Semin Immunol. 2011 Oct;23(5):368-78
references.pmid: 21920773