CCAAT/Enhancer Binding Protein Alpha in UVB Responses in Human and Mouse Skin and Mouse Skin Tumorigenesis

squamous cell carcinoma;cell cycle checkpoints;CCAAT/Enhancer Binding Protein alpha

Thompson, Elizabeth Ellen Anderson ; Dr. Robert C. Smart, Committee Chair,Thompson, Elizabeth Ellen Anderson ; Dr. Robert C. Smart ; Committee Chair

University:North Carolina State University

关键词: squamous cell carcinoma;    cell cycle checkpoints;    CCAAT/Enhancer Binding Protein alpha;   

Others  :  https://repository.lib.ncsu.edu/bitstream/handle/1840.16/6257/etd.pdf?sequence=1&isAllowed=y

美国|英语

来源: null

【 摘 要 】

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 alpha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.