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Hairless Suppresses Vitamin D Receptor Transactivation in Human Keratinocytes

Endocrine Unit, Veterans Affairs Medical Center, Northern California Institute for Research and Education and University of California, San Francisco, California 94121

Address all correspondence and requests for reprints to: Dr. Zhongjian Xie, Endocrine Unit, Veterans Affairs Medical Center, 4150 Clement Street (111N), San Francisco, California 94121. E-mail: zjxie{at}itsa.ucsf.edu.

The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)₂D₃. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)₂D₃. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)₂D₃, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)₂D₃ action on keratinocytes.

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