Figure 3.

Molecular mechanisms of Notch-mediated epidermal homeostasis. A schematic diagram depicting the intersecting pathways and downstream effectors during Notch-induced differentiation. Notch expression and/or signaling in epidermal keratinocytes are promoted by p53 and antagonized by AP-1, which represses p53 expression. Notch also represses AP-1 activity, suggesting that the Notch and AP-1 pathways are mutually antagonistic. Notch signaling subsequently promotes cell-cycle arrest of progenitor cells in the basal layer by repressing p63 and by inducing the expression of the cell-cycle inhibitor CDKN1a/p21. Differentiation is promoted by the induction of factors including IRF6 and the Hes/Hey family of transcriptional repressors. Notch also promotes RA signaling by inducing the expression of retinol-binding proteins such as CRABP2, FABP5, and CRBP-1. Activation of the RA pathway promotes the differentiation of the epidermal epithelium.