AP1 transcription factors in epidermal differentiation and skin cancer

Abstract

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.

Figure 1

MAPK and AP1 transcription factor control of gene expression. The p38δ MAPK cascade that controls the expression of differentiation-associated genes in epidermis is depicted [10]. The three kinases of the MAPK module include MEKK1, MEK3, and p38δ MAPK. A differentiation stimulus activates upstream regulatory proteins, in this case novel protein kinase c (nPKC) and the Ras small GTPase. These events lead to phosphorylation and activation of MEKK1 which phosphorylates MEK3 which phosphorylates p38δ MAPK. Ultimately p38δ MAPK increases AP1 transcription factor expression and activity and the AP1 transcription factors bind to the response element on the target gene promoter to increase transcription.