Role of c-fos and E2F in the induction of cyclin A transcription and vascular smooth muscle cell proliferation.
Role of c-fos and E2F in the induction of cyclin A transcription and vascular smooth muscle cell proliferation.
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DOI：
10.1172/jci1630
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发表时间：
1998-03
期刊：
影响因子：
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通讯作者：
Amy M. Sylvester;Dongfen Chen;K. Krasinski;V. Andrés
中科院分区：
文献类型：
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作者：
Amy M. Sylvester;Dongfen Chen;K. Krasinski;V. Andrés
血管平滑肌细胞(VSMCs)的过度增殖是血管成形术后血管再狭窄的重要原因。在这里，我们研究了周期蛋白A基因的转录调控，它是血管成形术后诱导的S期的关键正向调节因子。我们发现，依赖RAS的有丝分裂信号对于正常刺激VSMCs中细胞周期蛋白A启动子活性和DNA合成是必不可少的。AP-1转录因子c-fos的过表达可以通过与Cyclin A启动子中的cAMP反应元件(Cre)相互作用来规避这一要求。此外，在血清饥饿的VSMCs中，c-fos的过表达导致细胞周期蛋白A启动子的活性以Cre依赖的方式被诱导，并且内源性c-fos蛋白与细胞周期蛋白A Cre的结合增加先于血清和体内血管成形术诱导的DNA复制。我们还表明，E2F功能对于依赖血清和c-fos诱导细胞周期蛋白A的表达是必不可少的。综上所述，这些发现表明，c-fos和E2F是VSMC中将RAS活性与Cyclin A转录联系起来的信号级联的重要组成部分。这些研究阐明了转录和细胞周期机制之间的新联系，这可能与血管增生性疾病的发病机制有关。
Excessive proliferation of vascular smooth muscle cells (VSMCs) contributes to vessel renarrowing after angioplasty. Here we investigated the transcriptional regulation of the cyclin A gene, a key positive regulator of S phase that is induced after angioplasty. We show that Ras-dependent mitogenic signaling is essential for the normal stimulation of cyclin A promoter activity and DNA synthesis in VSMCs. Overexpression of the AP-1 transcription factor c-fos can circumvent this requirement via interaction with the cAMP-responsive element (CRE) in the cyclin A promoter. Moreover, c-fos overexpression in serum-starved VSMCs results in the induction of cyclin A promoter activity in a CRE-dependent manner, and increased binding of endogenous c-fos protein to the cyclin A CRE precedes the onset of DNA replication in VSMCs induced by serum in vitro and by angioplasty in vivo. We also show that E2F function is essential for both serum- and c-fos-dependent induction of cyclin A expression. Taken together, these findings suggest that c-fos and E2F are important components of the signaling cascade that link Ras activity to cyclin A transcription in VSMCs. These studies illustrate a novel link between the transcriptional and cell cycle machinery that may be relevant to the pathogenesis of vascular proliferative disorders.