Rodriguez-Puebla M L, Robles A I, Conti C J
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
Mol Carcinog. 1999 Jan;24(1):1-6.
ras is a family of small GTP-binding proteins that transduce signals from tyrosine-kinase receptors to the nucleus and thus play a role in the regulation of cell proliferation and differentiation. Several lines of evidence have shown that the cell-cycle machinery, specifically the circuit cyclin D1/cyclin-dependent kinase (cdk) 4 and 6-p16-pRb, lies downstream of ras. Point mutations that activate the ras protein and its downstream cascade have been observed in human and experimental tumors. In particular, ras mutations have been well characterized in the mouse skin two-stage carcinogenesis model, and a large body of literature has indicated that initiation with the genotoxic carcinogen 7,12-dimethylbenz[a]anthracene induces a specific point mutation in Ha-ras gene in this model. In the last few years, several studies have shown a correlation between ras activation and alterations in the expression of cyclin D1 as well as other cell cycle-regulated proteins, but the actual role of these alterations in tumor development had not been determined until a recent study provided genetic and biochemical evidence that cyclin D1 is a critical target of oncogenic ras in mouse skin carcinogenesis. Here we review these results, including the evidence that cyclin D1 has a role as a downstream mediator of ras activity during tumor development. We propose a model in which cyclin D1 has a unique growth-promoting role in tumor development but does not act as an oncogene independently of ras activity.
Ras是一类小的GTP结合蛋白家族，它将信号从酪氨酸激酶受体传导至细胞核，从而在细胞增殖和分化的调节中发挥作用。多项证据表明，细胞周期机制，特别是细胞周期蛋白D1/细胞周期蛋白依赖性激酶（cdk）4和6-p16-pRb通路，位于Ras下游。在人类肿瘤和实验性肿瘤中已观察到激活Ras蛋白及其下游级联反应的点突变。特别是，Ras突变在小鼠皮肤两阶段致癌模型中已得到充分表征，大量文献表明，用遗传毒性致癌物7,12-二甲基苯并[a]蒽启动该模型会在Ha-ras基因中诱导特定的点突变。在过去几年中，多项研究表明Ras激活与细胞周期蛋白D1以及其他细胞周期调节蛋白表达的改变之间存在关联，但直到最近一项研究提供了遗传和生化证据表明细胞周期蛋白D1是小鼠皮肤致癌过程中致癌Ras的关键靶点，这些改变在肿瘤发生中的实际作用才得以确定。在此，我们综述这些结果，包括细胞周期蛋白D1在肿瘤发生过程中作为Ras活性下游介质发挥作用的证据。我们提出一个模型，其中细胞周期蛋白D1在肿瘤发生中具有独特的促进生长作用，但并非独立于Ras活性而作为癌基因发挥作用。
