Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators.
Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators.
复制标题
DOI：
10.1016/j.jmb.2008.08.071
复制
发表时间：
2008-11-28
影响因子：
5.6
通讯作者：
Benveniste, Etty N.
中科院分区：
文献类型：
--
作者：
Zhao, Xueyan;Benveniste, Etty N.
基质金属蛋白酶-9 （Matrix metalloproteinase-9, MMP-9）是一种基质蛋白、趋化因子和细胞因子的蛋白水解酶，由于其异常上调，是癌症和自身免疫性疾病的主要靶点。为了在病理条件下控制MMP-9的表达，有必要了解MMP-9表达的调控机制。MMP-9基因的表达主要在转录水平受到调控。在这项研究中，我们研究了多种共激活因子在调节MMP-9转录中的作用。我们证明了多个转录共激活因子参与MMP-9启动子的激活，包括CBP/p300、PCAF、CARM1和GRIP1。此外，MMP-9启动子活性的增强需要PCAF的组蛋白乙酰转移酶活性，而不需要CBP/p300的组蛋白乙酰转移酶活性和CARM1的甲基转移酶活性。更重要的是，这些共激活因子不仅能够独立激活MMP-9启动子活性，而且能够协同发挥作用。CARM1、p300和GRIP1之间存在显著的协同作用，这依赖于p300和CARM1分别与GRIP1的AD1和AD2结构域的相互作用。这表明在MMP-9启动子上形成了三元共激活物复合物。染色质免疫沉淀试验表明，这些共激活因子与内源性MMP-9启动子相关，siRNA敲低这些共激活因子的表达可降低内源性MMP-9的表达。综上所述，这些研究表明通过协同激活因子的协同作用对MMP-9表达的转录调控达到了一个新的水平。
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 coactivators in regulating MMP-9 transcription. We demonstrate that multiple transcriptional coactivators 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 coactivators are not only able to activate MMP-9 promoter activity independently, but also 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 coactivator complex on the MMP-9 promoter. Chromatin immunoprecipitation assays demonstrate that these coactivators associate with the endogenous MMP-9 promoter, and that siRNA knockdown of expression of these coactivators 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 coactivators.
登录
查看更多内容
影响因子：
14.9
作者：
Bordoli, L;Hüsser, S;Eckner, R
通讯作者：
Eckner, R
影响因子：
11.4
作者：
Chevillard-Briet, M;Trouche, D;Vandel, L
通讯作者：
Vandel, L
影响因子：
64.8
作者：
Bannister, AJ;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
9.2
作者：
Daujat, S;Bauer, UM;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
4.8
作者：
Chen, DG;Huang, SM;Stallcup, MR
通讯作者：
Stallcup, MR