title: Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhao
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: 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
chemical_list: 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
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