| Human epidermis is routinely subjected to DNA damage induced by solar radiation and keratinocytes have developed intricate mechanisms to respond to UVB-induced DNA damage. Despite these mechanisms, nonmelanoma skin cancer is the most common cancer in the US. Previous analysis of immortalized mouse keratinocytes has revealed that the bZIP transcription factor, CCAAT/enhancer binding protein alpha (C/EBPalpha), is induced by DNA damage and has a role in the G1 checkpoint. Here we demonstrate C/EBPalpha is induced in the epidermis of the human subjects exposed to UVB. To begin to determine the in vivo physiological significance of the up-regulation of C/EBPalpha by UVB, we generated an epidermal specific C/EBPalpha knockout (K5Cre;C/EBPalphafl/fl) mouse on a SKH1 hairless background. Following UVB treatment, these mice displayed an impaired keratinocyte cycle arrest and abnormal entry of keratinocytes into S-phase. This impaired cell cycle checkpoint in UVB-treated C/EBPalpha deficient skin was associated with greatly diminished p21 levels which occurred through a p53-independent mechanism. To further investigate whether C/EBPalpha could function as a tumor suppressor gene in UVB induced skin tumorigenesis, we exposed K5Cre;C/EBPalphafl/fl and K5Cre control SKH1 mice to 20mJ/cm2 UVB three times weekly. The K5Cre;C/EBPalphafl/fl mice displayed both increased tumor incidence and multiplicity, suggesting that loss of C/EBPalpha in the epidermis confers increased susceptibility to UVB-induced skin tumorigenesis. In addition, we also observed that human skin SCC and BCC display greatly reduced or absent C/EBPalpha levels, implicating that loss of C/EBPalpha contributes to the development of human nonmelanoma skin cancers. Collectively, our results demonstrate that C/EBPalpha is induced by UVB in human skin, inhibits cell cycle progression in response to UVB in vivo and is a tumor suppressor gene in UVB induced skin tumorigenesis. |
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