title: Opposing effects of KLF5 on the transcription of MYC in epithelial proliferation in the context of transforming growth factor beta.
abstract: The proto-oncogene MYC plays a critical role in cell proliferation and tumorigenesis, and its down-regulation by transforming growth factor beta (TGFbeta) signaling is necessary for TGFbeta to inhibit cell proliferation. KLF5, on the other hand, is a pro-proliferative basic transcription factor that reverses function to become an anti-proliferative TGFbeta cofactor upon TGFbeta stimulation in epithelial homeostasis. In this study we investigated whether KLF5 directly regulates MYC transcription in epithelial cells in the context of TGFbeta. Knockdown of KLF5 significantly reduced MYC expression in the HaCaT epidermal epithelial cells. When TGFbeta was applied, however, whereas MYC expression was significantly inhibited, knockdown of KLF5 increased MYC expression. Furthermore, re-expression of KLF5 restored the inhibitory effect of TGFbeta on MYC expression in two cancer cell lines. Chromatin immunoprecipitation and oligo pulldown experiments demonstrated that whereas binding of KLF5 to both KLF5 binding element (KBE) and TGFbeta inhibitory element (TIE) DNA elements was necessary for MYC transcription, binding to KBE was decreased by TGFbeta, and binding to TIE was increased by TGFbeta. These results suggest that KLF5 is not only essential for MYC transcription in proliferating epithelial cells but also mediates the inhibitory effect of TGFbeta on MYC transcription. Furthermore, different binding sites mediate different effects of KLF5 in the context of TGFbeta.
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Dong
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Kewen
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Qunna
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322. Electronic address: jdong2@emory.edu.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Dong
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta
references.citation: Nature. 2007 Jul 19;448(7151):318-24
references.pmid: 17554336
references.citation: Oncogene. 1999 Aug 26;18(34):4870-8
references.pmid: 10490820
references.citation: Mol Cell Biol. 2003 Dec;23(23):8528-41
references.pmid: 14612398
references.citation: Prostate. 2003 May 1;55(2):81-8
references.pmid: 12661032
references.citation: Mol Cell. 2002 Jan;9(1):133-43
references.pmid: 11804592
references.citation: Oncogene. 2002 Sep 26;21(43):6567-72
references.pmid: 12242654
references.citation: Oncogene. 2005 May 5;24(20):3319-27
references.pmid: 15735697
references.citation: Nat Rev Cancer. 2004 Jul;4(7):562-8
references.pmid: 15229481
references.citation: Nat Med. 2002 Aug;8(8):856-63
references.pmid: 12101409
references.citation: J Cell Sci. 2008 Aug 15;121(Pt 16):2629-34
references.pmid: 18653541
references.citation: Cell. 2000 Oct 13;103(2):295-309
references.pmid: 11057902
references.citation: Nat Genet. 2001 Jun;28(2):165-8
references.pmid: 11381265
references.citation: Cancer Res. 2000 Jun 1;60(11):3031-8
references.pmid: 10850453
references.citation: J Biol Chem. 2005 Dec 16;280(50):41553-61
references.pmid: 16223724
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):992-9
references.pmid: 11158583
references.citation: Nature. 2007 Jul 19;448(7151):313-7
references.pmid: 17554338
references.citation: Nat Rev Cancer. 2002 Oct;2(10):764-76
references.pmid: 12360279
references.citation: J Cell Biol. 1988 Mar;106(3):761-71
references.pmid: 2450098
references.citation: Mol Cell Biol. 2004 Mar;24(6):2546-59
references.pmid: 14993291
references.citation: J Biol Chem. 2001 Sep 14;276(37):34355-8
references.pmid: 11443140
references.citation: J Biol Chem. 2009 Jul 3;284(27):18184-93
references.pmid: 19419955
references.citation: J Cell Sci. 2006 Sep 1;119(Pt 17):3593-601
references.pmid: 16912082
references.citation: Nat Cell Biol. 2008 Mar;10(3):353-60
references.pmid: 18264089
references.citation: Nature. 2008 Jan 10;451(7175):141-6
references.pmid: 18157115
references.citation: Curr Biol. 2001 Apr 17;11(8):558-68
references.pmid: 11369200
references.citation: Nat Rev Cancer. 2003 Nov;3(11):807-21
references.pmid: 14557817
references.citation: Cell Stem Cell. 2008 Nov 6;3(5):555-67
references.pmid: 18983969
references.citation: Trends Cell Biol. 2005 Mar;15(3):128-37
references.pmid: 15752976
references.citation: J Biol Chem. 2009 Mar 6;284(10):6071-8
references.pmid: 19056724
references.citation: Mol Cell. 1999 May;3(5):565-77
references.pmid: 10360173
references.citation: Oncogene. 2007 Apr 5;26(16):2386-94
references.pmid: 17016436
references.citation: J Biol Chem. 2004 Mar 26;279(13):12093-101
references.pmid: 14726538
references.citation: Nat Cell Biol. 2001 Apr;3(4):392-9
references.pmid: 11283613
references.citation: Cancer Res. 1991 Aug 1;51(15):3996-4000
references.pmid: 1855215
references.citation: J Biol Chem. 1988 Sep 5;263(25):12705-8
references.pmid: 3045126
references.citation: Mol Cell Biol. 1999 Sep;19(9):5913-22
references.pmid: 10454538
references.citation: J Cell Physiol. 2001 Aug;188(2):143-60
references.pmid: 11424081
references.citation: Mol Carcinog. 1998 Nov;23(3):144-58
references.pmid: 9833775
references.citation: Cell. 2002 Jul 12;110(1):19-32
references.pmid: 12150994
references.citation: Gastroenterology. 2008 Jan;134(1):120-30
references.pmid: 18054006
references.citation: Eur J Cell Biol. 2002 Jun;81(6):323-34
references.pmid: 12113473
references.citation: Adv Cancer Res. 1996;68:109-82
references.pmid: 8712067
references.citation: Cancer Res. 1995 Apr 1;55(7):1452-7
references.pmid: 7882352
references.citation: J Biol Chem. 2002 Jan 4;277(1):854-61
references.pmid: 11689553
references.citation: Nat Cell Biol. 2001 Apr;3(4):400-8
references.pmid: 11283614
references.citation: Int J Cancer. 2006 Mar 15;118(6):1346-55
references.pmid: 16184550
references.citation: J Biol Chem. 2004 Jan 2;279(1):70-6
references.pmid: 14573617