IKK1 Control of Epidermal Differentiation Is Modulated by Notch Signaling

The molecular mechanism by which IκB kinase 1 (IKK1) regulates epidermal differentiation and tumor suppression in the skin is not well understood. As two major regulatory signaling pathways that regulate epidermal homeostasis and differentiation, the p63 and Notch pathways were examined in Ikk1 mutant epidermis and keratinocytes. Ikk1 inactivation in keratinocytes resulted in increased p63 expression and repression of Notch signaling. The impaired differentiation of Ikk1−/− keratinocytes was partially rescued by overexpression of the active form of the Notch1 receptor, the Notch intracellular domain (NICD). In contrast, knockdown of p63 expression by RNA interference was unable to rescue the defect. These results suggest that, in the mammalian skin, IKK1 functions as a differentiation regulator and tumor suppressor through the Notch signaling pathway.