Cited2 modulates TGF-β-mediated upregulation of MMP9
Cited2 modulates TGF-β-mediated upregulation of MMP9
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DOI：
10.1038/sj.onc.1209552
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发表时间：
2006-09-01
期刊：
影响因子：
8
通讯作者：
Yang, Y-C
中科院分区：
文献类型：
--
作者：
Chou, Y-T;Wang, H.;Yang, Y-C
引用的（（C）下杠BP/p300-与谷氨酸相互作用的反式激活因子（（E）下杠）n/天冬氨酸（（D）下杠）-富含C-末端结构域）2，是一种CBP/p300结合转录共激活因子，不含典型的DNA结合结构域，涉及Rat 1细胞中细胞生长和恶性转化的控制。在这份报告中，我们提供的证据表明，Cited 2是一个重要的调节转化生长因子（TGF）-β信号。Cited 2的过表达增强TGF-β介导的含Smad结合元件的荧光素酶报告构建体SBE 4-Luc的转录。这可能通过Cited 2与Smads 2和3的直接物理关联发生，如免疫共沉淀、哺乳动物双杂交和谷胱甘肽S-转移酶下拉测定所支持的。与Smad 3结合的转录因子p300被证明进一步增强Cited 2和Smad 3之间的相互作用，以及Cited 2对Smad 3的转录反应。Cited 2增强Cited 2诱导的小鼠胚胎中TGF-β介导的基质金属蛋白酶9（MMP 9）的上调。broblasts Cited 2的过表达增强了TGF-β介导的MMP 9启动子报告基因活性。此外，在MDA-MB-231细胞中敲低Cited 2减弱了TGF-β介导的MMP 9上调和TGF-β介导的细胞侵袭。染色质免疫沉淀显示，Cited 2和Smad 3在TGF-β刺激后被募集到MMP 9启动子。这是第一次证明Cited 2作为Smad 3/p300相互作用的转录共激活因子在调节MMP 9的表达中起作用，MMP 9可以影响TGF-β介导的肿瘤细胞侵袭。
Cited ((C) under bar BP/p300-interacting transactivators with glutamic acid ((E) under bar )n/ aspartic acid ((D) under bar)-rich C-terminal domain) 2, which is a CBP/p300-binding transcription co-activator without typical DNA-binding domains, has been implicated in control of cell growth and malignant transformation in Rat1 cells. In this report, we provide evidence that Cited2 is an important regulator of transforming growth factor (TGF)-beta signaling. Overexpression of Cited2 enhanced TGF-beta-mediated transcription of a Smad-Binding Element-containing luciferase reporter construct, SBE4-Luc. This may occur through a direct physical association of Cited2 with Smads 2 and 3, as supported by co-immunoprecipitation, mammalian two-hybrid and glutathione S-transferase- pull down assays. The transcription factor p300, which binds to Smad3, was shown to further enhance the interaction between Cited2 and Smad3, and the transcriptional responses of Smad3 by Cited2 in reporter assays. Cited2 enhances TGF-beta-mediated upregulation of matrix metalloproteinase 9 (MMP9) in Cited2 inducible mouse embryo. broblasts. Overexpression of Cited2 enhanced TGF-beta-mediated MMP9 promoter reporter activity. Moreover, knockdown of Cited2 in MDA-MB-231 cells attenuated TGF-beta-mediated upregulation of MMP9 and TGF-beta-mediated cell invasion. Chromatin immunoprecipitation showed that Cited2 and Smad3 were recruited to MMP9 promoter upon TGF-beta stimulation. This is the first demonstration that Cited2 functions as a Smad3/p300-interacting transcriptional coactivator in modulating the expression of MMP9, which could affect tumor cell invasion mediated by TGF-beta.