Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 127, Issue 4, Pages 874-880Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.jid.5700624
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Funding
- NIAMS NIH HHS [R01 AR38386, R01 AR050023, P01 AR39448, R01 AR038386] Funding Source: Medline
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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.
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