Roper E, Weinberg W, Watt F M, Land H
Imperial Cancer Research Fund, London, UK.
EMBO Rep. 2001 Feb;2(2):145-50. doi: 10.1093/embo-reports/kve020.
In tumorigenesis of the skin, activated Ras co-operates with mutations that inactivate the tumour suppressor p53, but the molecular basis for this co-operation remains unresolved. Here we show that activation of the Raf/MAP kinase pathway in primary mouse keratinocytes leads to a p53 and p21Cip1-dependent cycle arrest and to terminal differentiation. Raf activation in keratinocytes lacking p53 or p21Cip1 genes leads to expression of differentiation markers, but the cells do not cease to proliferate. Thus, loss of p53 or p21Cip1 function is necessary to disable growth-inhibitory Raf/MAP kinase signalling. Activation of oncogenes, including Ras, has been reported to stabilize and activate p53 via induction of the tumour suppressor p19ARF. However, the response to Raf in p19ARFI-/- keratinocytes was indistinguishable from wild-type controls. Thus, p19ARF is not essential for Raf-induced p53 induction and cell cycle arrest in keratinocytes, indicating that oncogenes engage p53 activity via multiple mechanisms.
在皮肤肿瘤发生过程中，活化的Ras与使肿瘤抑制因子p53失活的突变协同作用，但这种协同作用的分子基础仍未解决。在此我们表明，原代小鼠角质形成细胞中Raf/丝裂原活化蛋白激酶（MAP）激酶途径的激活导致p53和p21Cip1依赖性的细胞周期停滞以及终末分化。在缺乏p53或p21Cip1基因的角质形成细胞中Raf激活导致分化标志物的表达，但细胞并未停止增殖。因此，p53或p21Cip1功能的丧失对于解除生长抑制性Raf/MAP激酶信号传导是必要的。据报道，包括Ras在内的癌基因的激活通过诱导肿瘤抑制因子p19ARF来稳定和激活p53。然而，p19ARF基因敲除的角质形成细胞对Raf的反应与野生型对照无明显差异。因此，p19ARF对于Raf诱导的角质形成细胞中p53的诱导和细胞周期停滞并非必不可少，这表明癌基因通过多种机制参与p53活性的调控。
