AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Various in vivo genetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development. 1. Introduction Keratinocytes are the major cell type responsible for the structure of the epidermis. They begin as stem cells in the basal epidermal layer and hair follicles [1–3]. During differentiation, as the cells migrate to the surface, cell division ceases and morphological changes ensue to produce the spinous, granular, transition, and cornified layers. Spinous layer cells are distinguished by the presence of desmosomal connections, whereas granular layer cells are characterized by the presence of granules that contain the products of keratinocyte differentiation. Differentiation of the granular layer cells results in the formation of the transition zone which separates the dead from living epidermal layers. It is in this zone that the cellular constituents are extensively enzymatically remodeled. This remodeling results in the covalent crosslinking of proteins to produce terminally differentiated corneocytes that form the skin surface [4, 5]. Achieving these morphological alterations relies on executing a preset program of differentiation that requires tight regulation of gene transcription [6]. The process of activation and suppression of gene transcription is controlled by a diverse family of regulators called transcription factors. Transcription factors mediate the final steps in the relay of information from the cell surface to the nucleus and the gene. This is accomplished by the interaction of the transcription factor with specific DNA elements that are usually located
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