CCAAT/Enhancer Binding Protein Alpha in UVB Responses in Human and Mouse Skin and Mouse Skin Tumorigenesis
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Date
2010-08-04
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Abstract
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/EBP alpha), is induced by DNA damage and has a role in the G1 checkpoint. Here we demonstrate C/EBP alpha 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/EBP alpha by UVB, we generated an epidermal specific C/EBP alpha knockout (K5Cre;C/EBP alpha fl/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/EBP alphaï€ deficient skin was associated with greatly diminished p21 levels which occurred through a p53-independent mechanism. To further investigate whether C/EBP alpha could function as a tumor suppressor gene in UVB induced skin tumorigenesis, we exposed K5Cre;C/EBP alpha fl/fl and K5Cre control SKH1 mice to 20mJ/cm2 UVB three times weekly. The K5Cre;C/EBP alpha fl/fl mice displayed both increased tumor incidence and multiplicity, suggesting that loss of C/EBP alpha 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/EBP alpha levels, implicating that loss of C/EBP alpha contributes to the development of human nonmelanoma skin cancers. Collectively, our results demonstrate that C/EBP alpha 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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squamous cell carcinoma, cell cycle checkpoints, CCAAT/Enhancer Binding Protein alpha
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Degree
PhD
Discipline
Toxicology
