Abstract
Abstract AP1 (jun/fos) factors comprise a family of transcriptional regulators (c-jun, junB, junD, c-fos, FosB, Fra-1 and Fra-2) that are key controllers of epidermal keratinocyte survival and differentiation, and are important drivers of cancer development. Previous studies indicate that targeted inactivation of epidermal basal layer AP1 factor function by expression of dominant-negative c-jun (TAM67) in the basal epidermis produces no overt phenotypic impact, but does inhibit UVB and carcinogen-dependent epidermal tumor formation. We hypothesized that the role of AP1 factors is likely to be different in basal versus suprabasal epidermis. To test this hypothesis, we targeted TAM67 to the suprabasal epidermis using a tetracycline-inducible construct. Induction of suprabasal TAM67 expression results in marked epidermal hyperproliferation and hyperkeratosis. This is characterized by expression of basal layer and hyperproliferation-associated keratins in the suprabasal epidermis, suggesting that the cells are undergoing incomplete differentiation. We further demonstrate global changes in the AP1 factor signaling including changes in level and subcellular distribution of selected AP1 factors. Surprisingly, these animals display reduced susceptibility to carcinogen-dependent tumor induction. These novel observations, which suggest that perturbing AP1 factor function in the basal versus suprabasal layer produces different biological outcomes, is cancer relevant and points to the complexity of AP1-associated regulation and that fact that AP1 factor function differs as the tissue differentiates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4201.
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