Lloyd A C, Obermüller F, Staddon S, Barth C F, McMahon M, Land H
Imperial Cancer Research Fund (ICRF), London, UK.
Genes Dev. 1997 Mar 1;11(5):663-77. doi: 10.1101/gad.11.5.663.
The cooperation of oncogenes in the transformation of primary rat Schwann cells is a strikingly synergistic process. We have explored the molecular mechanisms involved. Activation of an inducible Raf kinase results in morphologically transformed cells that are arrested in G1 via the induction of p21(CiP1) and subsequent inhibition of cyclin/cdk activity. In contrast, coexpression of SV40 large T (LT) or a dominant-negative mutant of p53 abolishes p21(CiP1) induction and alleviates the growth arrest. Moreover in this scenario, Raf activation results in an increase in the specific activity of cyclin/cdk complexes with Raf and LT cooperating to superinduce cyclin A/cdk2 activity and stimulate proliferation in the absence of mitogens. Thus, signaling by Raf and its cooperating partners converges at the regulation of cyclin/cdk complexes, with the cellular responses to Raf modulated by p53.
癌基因在原代大鼠雪旺细胞转化过程中的合作是一个显著的协同过程。我们已经探究了其中涉及的分子机制。可诱导型Raf激酶的激活会导致形态发生转化的细胞，这些细胞通过诱导p21（CiP1）并随后抑制细胞周期蛋白/细胞周期蛋白依赖性激酶（cyclin/cdk）活性而停滞在G1期。相比之下，SV40大T抗原（LT）或p53的显性负性突变体的共表达会消除p21（CiP1）的诱导并减轻生长停滞。此外，在这种情况下，Raf激活会导致细胞周期蛋白/细胞周期蛋白依赖性激酶复合物的比活性增加，Raf和LT协同作用以超诱导细胞周期蛋白A/细胞周期蛋白依赖性激酶2（cyclin A/cdk2）活性并在没有有丝分裂原的情况下刺激增殖。因此，Raf及其合作伙伴的信号传导在细胞周期蛋白/细胞周期蛋白依赖性激酶复合物的调节上汇聚，p53调节细胞对Raf的反应。
