D'Abaco Giovanna M, Hooper Steven, Paterson Hugh, Marshall Christopher J
Cancer Research UK Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
J Cell Sci. 2002 Dec 1;115(Pt 23):4607-16. doi: 10.1242/jcs.00161.
The Ras GTPase is a critical transducer of mitogenic signals ultimately leading to inactivation of the retinoblastoma (Rb) protein, but the molecular basis underlying Ras-dependent control of cell cycle kinetics remains to a great extent unknown. In an effort to further elucidate the role of Ras activation in cell cycle control, we have studied the role of the downstream Mek-ERK pathway in facilitating exit from the quiescent G0 state and passage through the G1/S transition. We have adopted a genetic approach in combination with U0126, an inhibitor of Mek activation to study the role of Mek in cell cycle progression. Here we report that whereas wild-type (Wt) mouse embryo fibroblasts (MEFs) depend on ERK activation to enter the cell cycle, Rb-deficient (Rb(-/-)) MEFs have a reduced requirement for ERK signalling. Indeed in the presence of U0126 we found that Rb-null MEFs can exit G0, make the G1/S transition and proliferate. Analysis of Rb-deficient tumour cell lines also revealed a reduced requirement for ERK signalling in asynchronous growth. We discuss the molecular mechanism that may underlie this escape from MAP kinase signalling.
Ras鸟苷三磷酸酶是有丝分裂原信号的关键转导分子，最终导致视网膜母细胞瘤（Rb）蛋白失活，但Ras依赖的细胞周期动力学调控的分子基础在很大程度上仍不清楚。为了进一步阐明Ras激活在细胞周期调控中的作用，我们研究了下游Mek-ERK通路在促进细胞从静止的G0状态退出并通过G1/S转换中的作用。我们采用了基因方法并结合U0126（一种Mek激活抑制剂）来研究Mek在细胞周期进程中的作用。在此我们报告，野生型（Wt）小鼠胚胎成纤维细胞（MEF）依赖ERK激活进入细胞周期，而Rb缺陷型（Rb(-/-)）MEF对ERK信号的需求降低。实际上，在存在U0126的情况下，我们发现Rb缺失的MEF能够退出G0期，进行G1/S转换并增殖。对Rb缺陷肿瘤细胞系的分析也显示，在异步生长中对ERK信号的需求降低。我们讨论了这种对MAP激酶信号逃逸的潜在分子机制。
