Winston J T, Coats S R, Wang Y Z, Pledger W J
Department of Cell Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Oncogene. 1996 Jan 4;12(1):127-34.
The ras proto-oncogene has been implicated during the formation of tumors in vivo as well as the transformation of cell lines in culture. Conditional expression of an activated ras mutant in Balb/c-3T3 fibroblasts failed to stimulate S phase entry in the absence of plasma-derived progression factors, but did shorten the G1 interval from 12 to 6 h and abrogate the normal proliferative requirement for platelet-derived growth factor. Ras-dependent alteration of the 3T3 cell cycle was accompanied by a dramatic increase in the expression of the G1 regulatory protein, cyclin D1, while expression of cyclin E and cyclin A proteins were only weakly induced. Cyclin/cdk complexes assembled in response to ectopic ras expression in the absence of growth factor stimulation bound the cdk inhibitory factor, Kip1, and were inactive. However, plasma-stimulated regulatory pathways functioned co-operatively with the oncogenic ras molecule to decrease Kip1 levels, induce the kinase activities associated with cyclins D, E and A, and trigger the initiation of DNA replication. Our results suggest that a ras-activated signal transduction pathway may link environmental mitogenic stimuli to the cell cycle machinery via modulation of G1 cyclin expression.
原癌基因ras在体内肿瘤形成以及培养细胞系的转化过程中均有涉及。在Balb/c - 3T3成纤维细胞中，激活的ras突变体的条件性表达在缺乏血浆衍生的促增殖因子时无法刺激细胞进入S期，但确实将G1期从12小时缩短至6小时，并消除了对血小板衍生生长因子的正常增殖需求。Ras依赖的3T3细胞周期改变伴随着G1调节蛋白细胞周期蛋白D1表达的显著增加，而细胞周期蛋白E和细胞周期蛋白A的表达仅被微弱诱导。在缺乏生长因子刺激的情况下，响应异位ras表达组装的细胞周期蛋白/细胞周期蛋白依赖性激酶（cyclin/cdk）复合物结合了cdk抑制因子Kip1，并且没有活性。然而，血浆刺激的调节途径与致癌性ras分子协同作用，以降低Kip1水平，诱导与细胞周期蛋白D、E和A相关的激酶活性，并触发DNA复制的起始。我们的结果表明，ras激活的信号转导途径可能通过调节G1细胞周期蛋白的表达将环境促有丝分裂刺激与细胞周期机制联系起来。
