Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells

Sporadic human tumors and the hereditary cancer predisposition syndrome Li- Fraumeni are frequently associated with mutations in the p53 tumor suppress or 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 th e p53 protein. This suggests that p53 may be kept inactive in human cancer by mutations targeting DNA damage signaling pathways. Melanoma cells are hi ghly radioresistant, yet they express wild-type p53 protein, raising the po ssibility of defects in the pathways that activate p53 in response to DNA d amage. We have described a chk2/hcds1-independent DNA damage signaling path way that targets Ser-376 within the COOH terminus of p53 for dephosphorylat ion and leads to increased p53 functional activity, We now report that in s everal human melanoma cell lines that express wild-type p53, the phosphoryl ation 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 w ild-type p53 led to cell cycle arrest or apoptosis, Thus, defective activat ion of p53 in response to DNA damage may underlie the radioresistance of hu man melanoma cells.