The Role of C/EBPa in Genome Stability and Tumor Progression

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DESCRIPTION (provided by applicant): Cancer is a disease that arises from genomic alterations in somatic cells and it is the accumulation of genetic alterations that drives tumorigenesis. Moreover, it is the rate at which a developing tumor cell acquires these genetic alterations that ultimately determines the onset of cancer. Human skin is routinely subjected to DNA damage induced by solar radiation and keratinocytes have developed intricate pathways to response to UVB-induced DNA damage. Recently, we provided the first genetic evidence CCAAT/enhancer binding protein 1 (C/EBP1), a member of the basic leucine zipper family of transcription factors, functions as an epithelial tumor suppressor through utilization of mice with an epidermal-targeted ablation of C/EBP1. These mice are highly susceptible to UVB- and carcinogen-induced squamous papilloma development and these benign skin tumors display a highly accelerated rate of malignant progression to squamous cell carcinomas. Human skin squamous cell carcinomas and basal cell carcinomas as well as mouse skin squamous carcinomas display weak or ablated expression of C/EBP1. Together these findings suggest a tumor suppressor function of C/EBP1 in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBP1 results in an impaired DNA damage-induced G1 checkpoint, resulting in the accumulation of somatic mutations and promoting skin cancer progression. The overall objective of this proposal is to understand how the loss of C/EBP1 contributes to an increased rate of malignant tumor progression focusing on the role of C/EBP1 in the DNA damage- induced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBP1 functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBP1 ablation. .