Regulation and Function of C/EBP in UVB Responses

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DESCRIPTION (provided by applicant): The basic leucine zipper (bZIP) transcription factor, CCAAT/enhancer binding protein-a/(C/EBPa) is abundantly expressed within keratinocytes of the epidermis, however relatively little is known regarding its function in skin. C/EBPa has been implicated as a human tumor suppressor in acute myeloid leukemia and our results in experimental systems suggest C/EBPa negatively regulates keratinocyte growth and may have a tumor suppressor function in skin tumorigenesis. Sunlight, more specifically the UVB component of sunlight, causes DMA damage and is responsible for the majority of human skin cancers. Keratinocytes can respond to UVB irradiation by undergoing cell cycle arrest, apoptosis and/or altered differentiation. We have discovered that UVB, as well as other DNA damaging agents, are potent inducers of C/EBPa expression in human and mouse keratinocytes and that this induction requires p53, Thus, we have identified C/EBPa as a novel p53-regulated DNA damage-inducible gene in human and mouse keratinocytes. The ability of cells to respond to DNA damage is essential to ensure the integrity of the genome. DNA damage can initiate the activation of cell cycle checkpoints that arrest cell cycle progression preventing replication of damaged DNA and allowing time for DNA repair. We hypothesize that UVB-induced C/EBPa has a DNA damage checkpoint function involving cell cycle arrest and we propose the loss of UVB-induced C/EBPa would enhance UVB carcinogenesis. While p53 is an absolute requirement for UVB-induced C/EBPa, we have observed that catalytically active GSK is also required. We propose that UVB-induction of C/EBPa involves direct binding of p53 to the C/EBPa promoter resulting in increased expression of C/EBPa and that nuclear GSK3 has a regulatory role in this process. Characterization of the biological function of C/EBPa in the UVB-response in keratinocytes as well as how the UVB signal is translated into the transcriptional up-regulation of C/EBPa will provide new insight into mechanisms of UVB-induced gene regulation, cellular responses and skin cancer.