Abstract
Abstract Genomic amplification and/or overexpression of the p63 gene are one of the most frequently observed abnormalities in human cutaneous and noncutaneous squamous cell carcinoma (SCC), however, in spite of several studies in genetically engineered mouse models and in human tumors, the contribution of p63 in SCC development is still controversial. As a member of the p53 family, p63 can bind to the canonical p53-binding site, transactivating or repressing a subset of p53 or p73 target genes in vivo, while it also affects a subset of specific target genes. In contrast to p53, p63, and more specifically its DeltaNp63 alpha isoform, has a tissue-restricted pattern of expression in stratified epithelia and its impact on tumorigenesis is likely to be tumor-specific as well. Here we present data indicating that p63 is required for proliferation and G1 progression in a p53 independent manner in mouse primary keratinocyte, as well as in mouse embryonic epidermis. In addition we identified a number of p63 early target genes that are involved in cell cycle progression and in DNA replication. Among direct p63 targets we identified members of a specific microRNA (miRNA) family that are highly expressed in the epidermis. p63 binds to their genomic regulatory regions thereby directly repressing their expression. Overexpression of these specific miRNA arrests cell proliferation, whereas specific anti-miRNA expression substantially rescues the cell proliferation defect in p63 ablated keratinocytes. We propose that control of this specific miRNA family by p63 may play a role in sustaining cell proliferation in SCC development. Citation Information: Cancer Res 2009;69(23 Suppl):A56.
Published Version
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