Evidence for Activation of the TGF-β1 Promoter by C/EBPβ and Its Modulation by Smads
Evidence for Activation of the TGF-β1 Promoter by C/EBPβ and Its Modulation by Smads
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DOI：
10.1089/jir.2008.0036
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发表时间：
2009-01-01
影响因子：
2.3
通讯作者：
Amini, Shohreh
中科院分区：
文献类型：
--
作者：
Abraham, Selvajothi;Sweet, Thersa;Amini, Shohreh
转化生长因子-β 1（transforming growth factor-beta 1，TGF-β 1）是一种细胞因子，参与免疫抑制、血管生成、细胞生长和凋亡等多种生物学过程。TGF-β 1在转录水平上的表达受一系列普遍存在的和专门的因子控制，这些因子的活性可以通过各种信号事件来调节。在这里，我们证明了活性的TGF-β 1启动子增加的C/EBP β，DNA结合转录因子，其活性可以受到几种免疫调节剂，在星形胶质细胞和小胶质细胞。有趣的是，TGF-β 1信号通路的下游调节因子Smad 3和Smad 4的表达损害了TGF-β 1启动子上C/EBP β的活性。此外，我们证明，MH 2，一个共同的结构域之间的Smads，具有蛋白质结合活性，与C/EBP β相互作用，并减少其与一个区域的TGF-β 1启动子，是响应于C/EBP β激活。有趣的是，核因子-κ B（NF-κ B）的p65亚基也与C/EBP β相互作用，与MH 2合作，降低TGF-β 1启动子上C/EBP β的DNA结合和转录活性。这些观察结果表明，涉及Smads的MH 2结构域的自动调节机制通过C/EBP β调节TGF-β 1启动子的激活。此外，我们的研究结果表明，NF-κ B和C/EBP β之间的相互作用对C/EBP β刺激TGF-β 1转录的能力有影响，因此，表明调节NF-κ B和C/EBP β的信号通路的交叉通信可能决定TGF-β 1启动子活性的水平。
The transforming growth factor-beta 1 (TGF-beta 1) is a cytokine involved in many biological events inlcuding immunosuppression, angiogenesis, cell growth, and apoptosis. Expression of TGF-beta 1 at the transcriptional level is controlled by a series of ubiquitous and specialized factors whose activities can be modulated by a variety of signaling events. Here we demonstrate that activity of the TGF-beta 1 promoter is increased by C/EBP beta, a DNA-binding transcription factor whose activity can be influenced by several immunomodulators, in astrocytes and microglial cells. Interestingly, expression of Smad3 and Smad4, the downstream regulators of the TGF-beta 1-signaling pathway, impairs the activity of C/EBP beta on the TGF-beta 1 promoter. Further, we demonstrate that MH2, a common domain among Smads that has protein-binding activities, interacts with C/EBP beta and decreases its association with a region of the TGF-beta 1 promoter that is responsive to C/EBP beta activation. Interestingly, the p65 subunit of nuclear factor-kappa B (NF-kappa B), which also interacts with C/EBP beta, cooperates with MH2 and decreased DNA-binding and transcriptional activities of C/EBP beta on the TGF-beta 1 promoter. These observations indicate that an autoregulatory mechanism, involving the MH2 domain of Smads, modulates activation of the TGF-beta 1 promoter by C/EBP beta. Further, our results show that the interplay between NF-kappa B and C/EBP beta has an impact on the ability of C/EBP beta to stimulate TGF-beta 1 transcription, hence, suggesting that the cross-communication of signaling pathways that modulate NF-kappa B and C/EBP beta may dictate the level of TGF-beta 1 promoter activity.