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首页> 外文期刊>Molecular and Cellular Biology >High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.
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High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

机译：高强度Raf信号引起p21Cip1介导的细胞周期停滞。

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Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.
机译：活化的Raf已经与诸如DNA合成的诱导和增殖抑制之类的相反的细胞反应相关。但是，尚不清楚如何调节这种信号特异性的开关。我们已经用鼠成纤维细胞中可调节的Raf-雄激素受体融合蛋白解决了这个问题。我们显示Raf可以通过诱导p21Cip1引起G1特异性细胞周期停滞。反过来，这导致细胞周期蛋白D和细胞周期蛋白E依赖性激酶的抑制和磷酸化Rb的积累。重要的是，只能响应强Raf信号才能观察到此行为。相反，中等的Raf活性诱导DNA合成，并且足以诱导细胞周期蛋白D表达。因此，Raf信号特异性可以通过信号强度的调节来确定，大概是通过诱导不同的蛋白质表达模式来进行的。与Raf的诱导相似，通过四环素依赖性启动子强烈诱导活化的Ras也会导致增殖抑制和高表达水平的p21Cip1诱导。因此，p21Cip1在确定细胞对Ras和Raf信号的反应中起关键作用。正如该发现所预测的，我们表明Ras和p21的丧失共同为小鼠胚胎成纤维细胞赋予了增殖优势。

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