Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers. In vitro keratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NFκB/c-Rel as a downstream effector of p63 has identified a role for NFκB/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression. 1. Introduction p53 is a tumor suppressor that is upregulated and activated across organ systems as a tissue protective stress response mechanism [1]. p63 is a member of the p53 gene family which also includes p73. In contrast to p53, both p63 and p73 exhibit cell-type-specific expression patterns and exert tissue-specific functions [2, 3]. Relevant to this review, p63 plays an essential role in the development and maintenance of normal stratified squamous epithelium. All p53 family members encode multiple protein isoforms that act in overlapping or opposing manners both within and across family members. Given the complexity of the p53 family and the potential for the different family members to mimic or interfere with each other, the balance of p53 family isoforms in a given cellular context can impact the biological outcome. In this review, we highlight how information derived from mouse models has provided insight into molecular mechanisms of normal keratinocyte growth regulation and human cancer pathogenesis. In particular, we focus on the p63 gene, the role of its gene products in normal epidermal development and homeostasis, and how dysregulation of p63 protein expression, which is tightly controlled under normal conditions, contributes to squamous carcinogenesis, not only of the skin, but also in other squamous epithelial cancers such as those of the head and
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