Warenius H M, Jones M, Gorman T, McLeish R, Seabra L, Barraclough R, Rudland P
Human Tumour Biology Group, University Clinical Departments, Oncology Research Unit, Department of Medicine, The University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA.
Br J Cancer. 2000 Oct;83(8):1084-95. doi: 10.1054/bjoc.2000.1409.
The tumour suppressor gene, p53, and genes coding for positive signal transduction factors can influence transit through cell-cycle checkpoints and modulate radiosensitivity. Here we examine the effects of RAF1 protein on the rate of exit from a G2/M block induced by gamma-irradiation in relation to intrinsic cellular radiosensitivity in human cell lines expressing wild-type p53 (wtp53) protein as compared to mutant p53 (mutp53) protein. Cell lines which expressed mutp53 protein were all relatively radioresistant and exhibited no relationship between RAF1 protein and cellular radiosensitivity. Cell lines expressing wtp53 protein, however, showed a strong relationship between RAF1 protein levels and the radiosensitivity parameter SF2. In addition, when post-irradiation perturbation of G2/M transit was compared using the parameter T50 (time after the peak of G2/M delay at which 50% of the cells had exited from a block induced by 2 Gy of irradiation), RAF1 was related to T50 in wtp53, but not mutp53, cell lines. Cell lines which expressed wtp53 protein and high levels of RAF1 had shorter T50s and were also more radiosensitive. These results suggest a cooperative role for wtp53 and RAF1 protein in determining cellular radiosensitivity in human cells, which involves control of the G2/M checkpoint.
肿瘤抑制基因p53以及编码正向信号转导因子的基因可影响细胞周期检查点的过渡并调节放射敏感性。在此，我们研究了RAF1蛋白对γ射线诱导的G2/M阻滞退出率的影响，并将其与表达野生型p53（wtp53）蛋白的人类细胞系和突变型p53（mutp53）蛋白的人类细胞系的内在细胞放射敏感性进行比较。表达mutp53蛋白的细胞系均相对具有放射抗性，且RAF1蛋白与细胞放射敏感性之间无关联。然而，表达wtp53蛋白的细胞系显示RAF1蛋白水平与放射敏感性参数SF2之间存在密切关系。此外，当使用参数T50（2 Gy照射诱导的阻滞达到G2/M延迟峰值后，50%的细胞从阻滞中退出的时间）比较照射后G2/M过渡的扰动时，RAF1与wtp53细胞系中的T50相关，但与mutp53细胞系无关。表达wtp53蛋白且RAF1水平高的细胞系T50较短，放射敏感性也更高。这些结果表明wtp53和RAF1蛋白在决定人类细胞的放射敏感性方面具有协同作用，这涉及对G2/M检查点的控制。
