p21 Cooperates with DDB2 Protein in Suppression of Ultraviolet Ray-induced Skin Malignancies

摘要

Exposure to ultraviolet rays (UV) in sunlight is the main cause of skin cancer. Here, we show that the p53-induced genes DDB2 and p21 are down-regulated in skin cancer, and in the mouse model they functionally cooperate to prevent UV-induced skin cancer. Our previous studies demonstrated an antagonistic role of DDB2 and p21 in nucleotide excision repair and apoptosis. Surprisingly, we find that the loss of p21 restores nucleotide excision repair and apoptosis in Ddb2^−/− mice, but it does not protect from UV-mediated skin carcinogenesis. In contrast, Ddb2^−/−p21^−/− mice are significantly more susceptible to UV-induced skin cancer than the Ddb2^−/− or the p21^−/− mice. We provide evidence that p21 deletion in the Ddb2^−/− background causes a strong increase in cell proliferation. The increased proliferation in the Ddb2^−/−p21^−/− background is related to a severe deficiency in UV-induced premature senescence. Also, the oncogenic pro-proliferation transcription factor FOXM1 is overexpressed in the p21^−/− background. Our results show that the anti-proliferative and the pro-senescence pathways of DDB2 and p21 are critical protection mechanisms against skin malignancies.