Human melanoma cell line UV responses show independency of p53 function

UV radiation-induced mutation of the p53 gene is suggested as a causative e vent in skin cancer, including melanoma. We have analyzed here p53 mutation s in melanoma cell lines and studied its stabilization, DNA-binding activit y, and target gene activation by UVC. p53 was mutated in three of seven mel anoma eel lines. However, high levels of p53 were detected in all cell line s, including melanoma cells with wild-type p53, with the exception of one l ine with a truncated form. Upon UV induction, p53 accumulated in lines with wild-type p53, and p53 target genes p21(Cip1/Waf1), GADD45, and mdm2 were induced, but the induction of p21(Cip1/Waf1) was significantly delayed as c ompared with the increase in p53 DNA-binding activity. However, despite p53 target gene induction, p53 DNA-binding activity was absent in one melanoma line with wild-type p53, and p53 target genes were induced also in cells w ith mutant p53. In response to UV, DNA replication ceased in all cell lines , and apoptosis ensued in four lines independently of p53 but correlated wi th high induction of GADD45. The results suggest that in melanoma, several p53 regulatory steps are dislodged; its basal expression is high, its activ ation in response to UV damage is diminished, and the regulation of its tar get genes p21(Cip1/Waf1) and GADD45 are dissociated from p53 regulation.