Satyamoorthy K, Chehab N H, Waterman M J, Lien M C, El-Deiry W S, Herlyn M, Halazonetis T D
The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
Cell Growth Differ. 2000 Sep;11(9):467-74.
Sporadic human tumors and the hereditary cancer predisposition syndrome Li-Fraumeni are frequently associated with mutations in the p53 tumor suppressor gene that compromise its ability to function as a DNA damage checkpoint. A subset of Li-Fraumeni patients with wild-type p53 alleles have mutations in chk2/hcds1, one of the genes signaling the presence of DNA damage to the p53 protein. This suggests that p53 may be kept inactive in human cancer by mutations targeting DNA damage signaling pathways. Melanoma cells are highly radioresistant, yet they express wild-type p53 protein, raising the possibility of defects in the pathways that activate p53 in response to DNA damage. We have described a chk2/hcds1-independent DNA damage signaling pathway that targets Ser-376 within the COOH terminus of p53 for dephosphorylation and leads to increased p53 functional activity. We now report that in several human melanoma cell lines that express wild-type p53, the phosphorylation state of Ser-376 was not regulated by DNA damage. In these cell lines, neither the endogenous wild-type p53 protein nor high levels of ectopic wild-type p53 led to cell cycle arrest or apoptosis. Thus, defective activation of p53 in response to DNA damage may underlie the radioresistance of human melanoma cells.
散发性人类肿瘤以及遗传性癌症易感性综合征李-佛美尼综合征常常与p53肿瘤抑制基因突变有关，这些突变损害了其作为DNA损伤检查点发挥功能的能力。一部分携带野生型p53等位基因的李-佛美尼综合征患者在chk2/hcds1基因发生了突变，chk2/hcds1基因是向p53蛋白传递DNA损伤信号的基因之一。这表明在人类癌症中，p53可能通过针对DNA损伤信号通路的突变而保持无活性状态。黑色素瘤细胞具有高度放射抗性，但它们表达野生型p53蛋白，这增加了在DNA损伤应答中激活p53的信号通路存在缺陷的可能性。我们已经描述了一条不依赖chk2/hcds1的DNA损伤信号通路，该通路作用于p53羧基末端的丝氨酸376使其去磷酸化，并导致p53功能活性增强。我们现在报告，在几种表达野生型p53的人类黑色素瘤细胞系中，丝氨酸376的磷酸化状态不受DNA损伤的调控。在这些细胞系中，内源性野生型p53蛋白以及高水平的异位野生型p53均未导致细胞周期停滞或凋亡。因此，DNA损伤应答中p53的激活缺陷可能是人类黑色素瘤细胞放射抗性的基础。
