Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators.
Matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme for matrix proteins, chemokines and cytokines, is a major target in cancer and autoimmune diseases, since it is aberrantly upregulated. To control MMP-9 expression in pathological conditions, it is necessary to understand the regulatory mechanisms of MMP-9 expression. MMP-9 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of multiple co-activators in regulating MMP-9 transcription. We demonstrate that multiple transcriptional co-activators are involved in MMP-9 promoter activation, including CBP/p300, PCAF, CARM1 and GRIP1. Furthermore, enhancement of MMP-9 promoter activity requires the histone acetyltransferase activity of PCAF but not that of CBP/p300, and the methyltransferase activity of CARM1. More importantly, these co-activators are able to activate MMP-9 promoter activity independently, and function in a synergistic manner. Significant synergy was observed among CARM1, p300 and GRIP1, which is dependent on the interaction of p300 and CARM1 with the AD1 and AD2 domains of GRIP1, respectively. This suggests the formation of a ternary co-activator complex on the MMP-9 promoter. Chromatin immunoprecipitation assays demonstrate that these co-activators associate with the endogenous MMP-9 promoter, and that siRNA knockdown of expression of these co-activators reduces endogenous MMP-9 expression. Taken together, these studies demonstrate a new level of transcriptional regulation of MMP-9 expression by the cooperative action of co-activators.
Zhao
Xueyan
X
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Benveniste
Etty N
EN
D050882:CREB-Binding Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D050882:CREB-Binding Protein; D002352:Carrier Proteins; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; D020780:Matrix Metalloproteinase 9; D009419:Nerve Tissue Proteins; D011484:Protein-Arginine N-Methyltransferases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C491310:GRIP1 protein, human; C119966:coactivator-associated arginine methyltransferase 1; C494360:EP300 protein, human
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16321-6
16254053
Science. 1999 Jun 25;284(5423):2174-7
10381882
EMBO J. 2002 Dec 2;21(23):6539-48
12456660
Nature. 1996 Jul 25;382(6589):319-24
8684459
Genes Dev. 2004 Jan 15;18(2):144-56
14729568
FEBS Lett. 2000 Nov 24;485(2-3):195-9
11094166
Mol Cell Biol. 2002 Jun;22(11):3621-32
11997499
J Cell Physiol. 2007 Apr;211(1):19-26
17167774
Science. 1997 Aug 15;277(5328):965-8
9252329
J Biol Chem. 1998 May 1;273(18):10831-4
9556555
J Biol Chem. 2001 Oct 5;276(40):36865-8
11459854
J Biol Chem. 2001 Apr 27;276(17):13505-8
11279224
Science. 1998 Jan 30;279(5351):703-7
9445475
Cancer. 2004 Jul 1;101(1):83-9
15221992
Nucleic Acids Res. 2001 Nov 1;29(21):4462-71
11691934
J Cell Sci. 2001 Jul;114(Pt 13):2363-73
11559745
Cell. 1997 Aug 8;90(3):569-80
9267036
J Biol Chem. 1998 Jul 3;273(27):16651-4
9642216
Biochemistry. 2001 May 15;40(19):5747-56
11341840
Cell. 2002 Feb 22;108(4):465-74
11909518
J Biol Chem. 2005 Jun 10;280(23):21882-92
15824107
J Immunol. 2001 Nov 1;167(9):5150-9
11673527
Mol Cell Biol. 1999 Sep;19(9):6164-73
10454563
Crit Rev Biochem Mol Biol. 2002 Dec;37(6):375-536
12540195
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13351-6
16938873
Cell. 1996 Nov 29;87(5):953-9
8945521
Science. 2001 Dec 21;294(5551):2507-11
11701890
J Mol Biol. 2008 Mar 28;377(3):668-78
18280497
Br J Cancer. 1999 Apr;79(11-12):1828-35
10206300
Mol Cell Biol. 2004 Jun;24(12):5496-509
15169910
Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
17318226
J Neurol. 2004 Jun;251 Suppl 2:II10-4
15264107
J Biol Chem. 1996 May 3;271(18):10672-80
8631874
EMBO Rep. 2002 Jan;3(1):39-44
11751582
J Cell Physiol. 2007 Nov;213(2):306-15
17708529
J Biol Chem. 2001 Jan 12;276(2):1089-98
11050077
FEBS J. 2007 Dec;274(24):6456-68
18028425
Endocr Rev. 2005 Apr;26(2):147-70
15479858
Cell. 2001 Mar 9;104(5):731-41
11257227
Genes Dev. 1994 Apr 15;8(8):869-84
7523245
EMBO J. 2002 Oct 15;21(20):5457-66
12374746
J Biol Chem. 2000 Dec 29;275(52):40810-6
11010967
EMBO J. 2005 Jan 12;24(1):85-96
15616592
Science. 2001 Aug 3;293(5531):853-7
11387442
Mol Endocrinol. 2003 Sep;17(9):1681-92
12805412
Mol Endocrinol. 2006 Jul;20(7):1562-73
16497732
Nat Rev Cancer. 2002 Mar;2(3):161-74
11990853
Cell. 1997 Aug 22;90(4):595-606
9288740
Curr Biol. 2002 Dec 23;12(24):2090-7
12498683
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):2927-32
9096323
Oncogene. 2003 Nov 13;22(51):8316-29
14614455
Nature. 1996 Dec 19-26;384(6610):641-3
8967953
EMBO J. 1998 Jan 15;17(2):507-19
9430642
Mol Cell Biol. 1999 Sep;19(9):6367-78
10454583