Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3.
It has long been known that the active metabolite of vitamin D, 1,25 dihydroxyvitamin D(3), stimulates differentiation and inhibits proliferation in epidermal keratinocytes through interaction with the vitamin D receptor (VDR). VDR functions through the coordinate binding of vitamin D response elements in the DNA and specific coactivator proteins which help to initiate transcription. It was recently observed that VDR binds to two major coactivator complexes, DRIP (VDR-interacting protein) and SRC (steroid receptor coactivator), during keratinocyte differentiation. To determine the role of VDR and its coactivators in mediating keratinocyte differentiation, we developed an adenoviral system to knock down, or in the case of VDR, overexpress these genes. In order to study all stages of keratinocyte development, we employed an advanced differentiated normal human keratinocyte culture system that produces a multilayer phenotype similar to that of normal skin. These studies have shown that VDR, DRIP, and SRC are all required for promotion of both early and late keratinocyte differentiation. Additionally, each individual differentiation marker that was assayed has a different specificity for the coactivators that regulate its expression.
Hawker
Nathaniel P
NP
Department of Medicine, Endocrine Research Unit, University of California and Veterans Affairs Medical Center, San Francisco, California, USA.
Pennypacker
Sally D
SD
Chang
Sandra M
SM
Bikle
Daniel D
DD
D000256:Adenoviridae / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005821:Genetic Techniques; D005822:Genetic Vectors; D051548:Histone Acetyltransferases / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D056913:Mediator Complex Subunit 1; D051958:Nuclear Receptor Coactivator 2 / Q000502:physiology*; D056921:Nuclear Receptor Coactivator 3; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D015415:Biomarkers; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D051958:Nuclear Receptor Coactivator 2; D018167:Receptors, Calcitriol; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3