Opposing effects of KLF5 on the transcription of MYC in epithelial proliferation in the context of transforming growth factor beta.
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.
Guo
Peng
P
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
Dong
Xue-Yuan
XY
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
Zhao
Kewen
K
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
Sun
Xiaodong
X
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
Li
Qunna
Q
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322.
Dong
Jin-Tang
JT
Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322. Electronic address: jdong2@emory.edu.
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*
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
Nature. 2007 Jul 19;448(7151):318-24
17554336
Oncogene. 1999 Aug 26;18(34):4870-8
10490820
Mol Cell Biol. 2003 Dec;23(23):8528-41
14612398
Prostate. 2003 May 1;55(2):81-8
12661032
Mol Cell. 2002 Jan;9(1):133-43
11804592
Oncogene. 2002 Sep 26;21(43):6567-72
12242654
Oncogene. 2005 May 5;24(20):3319-27
15735697
Nat Rev Cancer. 2004 Jul;4(7):562-8
15229481
Nat Med. 2002 Aug;8(8):856-63
12101409
J Cell Sci. 2008 Aug 15;121(Pt 16):2629-34
18653541
Cell. 2000 Oct 13;103(2):295-309
11057902
Nat Genet. 2001 Jun;28(2):165-8
11381265
Cancer Res. 2000 Jun 1;60(11):3031-8
10850453
J Biol Chem. 2005 Dec 16;280(50):41553-61
16223724
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):992-9
11158583
Nature. 2007 Jul 19;448(7151):313-7
17554338
Nat Rev Cancer. 2002 Oct;2(10):764-76
12360279
J Cell Biol. 1988 Mar;106(3):761-71
2450098
Mol Cell Biol. 2004 Mar;24(6):2546-59
14993291
J Biol Chem. 2001 Sep 14;276(37):34355-8
11443140
J Biol Chem. 2009 Jul 3;284(27):18184-93
19419955
J Cell Sci. 2006 Sep 1;119(Pt 17):3593-601
16912082
Nat Cell Biol. 2008 Mar;10(3):353-60
18264089
Nature. 2008 Jan 10;451(7175):141-6
18157115
Curr Biol. 2001 Apr 17;11(8):558-68
11369200
Nat Rev Cancer. 2003 Nov;3(11):807-21
14557817
Cell Stem Cell. 2008 Nov 6;3(5):555-67
18983969
Trends Cell Biol. 2005 Mar;15(3):128-37
15752976
J Biol Chem. 2009 Mar 6;284(10):6071-8
19056724
Mol Cell. 1999 May;3(5):565-77
10360173
Oncogene. 2007 Apr 5;26(16):2386-94
17016436
J Biol Chem. 2004 Mar 26;279(13):12093-101
14726538
Nat Cell Biol. 2001 Apr;3(4):392-9
11283613
Cancer Res. 1991 Aug 1;51(15):3996-4000
1855215
J Biol Chem. 1988 Sep 5;263(25):12705-8
3045126
Mol Cell Biol. 1999 Sep;19(9):5913-22
10454538
J Cell Physiol. 2001 Aug;188(2):143-60
11424081
Mol Carcinog. 1998 Nov;23(3):144-58
9833775
Cell. 2002 Jul 12;110(1):19-32
12150994
Gastroenterology. 2008 Jan;134(1):120-30
18054006
Eur J Cell Biol. 2002 Jun;81(6):323-34
12113473
Adv Cancer Res. 1996;68:109-82
8712067
Cancer Res. 1995 Apr 1;55(7):1452-7
7882352
J Biol Chem. 2002 Jan 4;277(1):854-61
11689553
Nat Cell Biol. 2001 Apr;3(4):400-8
11283614
Int J Cancer. 2006 Mar 15;118(6):1346-55
16184550
J Biol Chem. 2004 Jan 2;279(1):70-6
14573617