Differential role of two VDR coactivators, DRIP205 and SRC-3, in keratinocyte proliferation and differentiation.
Cell programs such as proliferation and differentiation involve the selective activation and repression of gene expression. The vitamin D receptor (VDR), through 1,25(OH)(2)D(3), controls the proliferation and differentiation of keratinocytes. Previously, we have identified two VDR binding coactivator complexes. In proliferating keratinocytes VDR bound preferentially to the DRIP complex, whereas in differentiated keratinocytes the SRC complex was preferred. We proposed that different coactivators are required for sequential gene regulation in the transition from proliferation to differentiation. Here we examined the roles of DRIP205 and SRC-3 in this transition. Silencing of DRIP205 and VDR caused hyperproliferation of keratinocytes, demonstrated by increased XTT and BrdU incorporation. SRC-3 silencing, on the other hand, did not have an effect on proliferation. In contrast, SRC-3 as well as DRIP205 and VDR silencing blocked keratinocyte differentiation as shown by decreased expression of keratin 1 and filaggrin. These results are consistent with the differential localization of DRIP205 and SRC-3 in skin. These results indicate that DRIP205 is required for keratinocyte proliferation. Both DRIP205 and SRC-3 are required for the keratinocyte differentiation. These results support the concept that the selective use of coactivators by VDR underlies the selective regulation of gene expression in keratinocyte proliferation and differentiation.
Oda
Yuko
Y
Departments of Medicine and Endocrinology, University of California-San Francisco, and Veterans Affairs Medical Center San Francisco, 41150 Clement Street, San Francisco, CA 94121, USA. yuko.oda@ucsf.edu
Ishikawa
Mieko H
MH
Hawker
Nathaniel P
NP
Yun
Qian-Chun
QC
Bikle
Daniel D
DD
D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D000091344:Filaggrin Proteins; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D056913:Mediator Complex Subunit 1; D056921:Nuclear Receptor Coactivator 3; D034741:RNA, Small Interfering / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3