Differential Role of VDR Coactivators SRC3 and MED1 in Regulating Skin Homeostasis = Differential Role of VDR Coactivators SRC3 and MED1 in Regulating Skin Homeostasis

다국어 초록 (Multilingual Abstract)

The vitamin D receptor (VDR) participates in skin homeostasis maintenance by modulating sequential expression of a number of genes involved in proliferation, differentiation, barrier function, and immune response, etc. This process is under precise regulation of coactivators and corepressors, activating or inhibiting the transcription activity of VDR in specific spatio-temporal fashion. In keratinocytes, the major coactivator complexes include the vitamin D receptor interacting protein (DRIP, or Mediator) complex and steroid receptor coactivator (SRC) complex. MED1, a subunit of Mediator that that binds directly to VDR, is abundantly expressed in proliferating keratinocytes. We found that MED1 had a specific role in the regulation of epidermal stem cell self-renewal, keratinocyte proliferation and differentiation ability by modulating the activation of β-catenin signaling pathways. SRC3, on the other hand, regulates the ability of 1,25(OH)2D3 to induce functions in the more differentiated keratinocyte such as lipid synthesis and processing required for permeability barrier formation and innate immune response triggered by disruption of the barrier. Therefore, we provide evidence to show that alternative combination of MED1 or SRC3 with VDR could regulate the on and off of target genes expression, selectively control different VDR functions, and achieve the skin homeostasis maintenance in diverse layers of skin.