The Transcriptional Coactivator DRIP/Mediator Complex Is Involved in Vitamin D Receptor Function and Regulates Keratinocyte Proliferation and Differentiation

Department of Medicine and Endocrinology, University of California, San Francisco and Veterans Affairs Medical Center San Francisco, San Francisco, California 94121, USA.
Journal of Investigative Dermatology (Impact Factor: 6.37). 10/2010; 130(10):2377-88. DOI: 10.1038/jid.2010.148
Source: PubMed

ABSTRACT Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors. We investigated the role of the mediator complex as a coactivator for vitamin D receptor (VDR) in keratinocytes. Using VDR affinity beads, the vitamin D receptor interacting protein (DRIP)/mediator complex was purified from primary keratinocytes, and its subunit composition was determined by mass spectrometry. The complex included core subunits, such as DRIP205/MED1 (MED1), that directly binds to VDR. Additional subunits were identified that are components of the RNA polymerase II complex. The functions of different mediator components were investigated by silencing its subunits. The core subunit MED1 facilitates VDR activity and regulating keratinocyte proliferation and differentiation. A newly described subunit MED21 also has a role in promoting keratinocyte proliferation and differentiation, whereas MED10 has an inhibitory role. Blocking MED1/MED21 expression caused hyperproliferation of keratinocytes, accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and/or glioma-associated oncogene homolog. Blocking MED1 or MED21 expression also resulted in defects in calcium-induced keratinocyte differentiation, as indicated by decreased expression of differentiation markers and decreased translocation of E-cadherin to the membrane. These results show that keratinocytes use the transcriptional coactivator mediator to regulate VDR functions and control keratinocyte proliferation and differentiation.

Download full-text


Available from: Alma L Burlingame, Jun 04, 2014
  • Source
    • "The epidermal marker FLG is over-expressed in hair follicles (utricles) as is caspase 14 in the IFE in VDR null skin (Bikle et al., 2006). On the other hand, deletion of MED1 caused hyper-proliferation of keratinocytes in the epidermis, consistent to our in vitro results (Oda et al., 2010) and similar to that seen in the VDR null mouse skin. Increased proliferation of keratinocytes in IFE in the MED1 null skin may predispose to epidermal tumorigenesis as seen in the VDR null mouse model (Ellison et al., 2008; Teichert et al., 2011; Zinser et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptional coactivator complex Mediator (MED) facilitates transcription of nuclear hormone receptors and other transcription factors. We have previously isolated the MED complex from primary keratinocytes (KCs) as the vitamin D receptor-interacting protein complex. We identified a role for MED in KC proliferation and differentiation in cultured KCs. Here, we investigated the in vivo role of MED by generating a conditional null mice model in which a critical subunit of the MED complex, MED1, is deleted from their KCs. The MED1 ablation resulted in aberrant hair differentiation and cycling, leading to hair loss. During the first hair follicle (HF) cycle, MED1 deletion resulted in a rapid regression of the HFs. Hair differentiation was reduced, and β-catenin/vitamin D receptor (VDR)-regulated gene expression was markedly decreased. In the subsequent adult hair cycle, MED1 ablation activated the initiation of HF cycling. Shh signaling was increased, but terminal differentiation was not sufficient. Deletion of MED1 also caused hyperproliferation of interfollicular epidermal KCs, and increased the expression of epidermal differentiation markers. These results indicate that MED1 has a critical role in regulating hair/epidermal proliferation and differentiation.
    Journal of Investigative Dermatology 12/2011; 132(4):1075-83. DOI:10.1038/jid.2011.430 · 6.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It is presented here that in order to fully understand the totality of intelligence, Level of Consciousness must be assessed, in addition to IQ. This study investigated whether people who participate in different mindfulness training activities (involvement in meditation, religion/spiritual discipline, martial arts, and yoga) have a higher level of consciousness
    Procedia - Social and Behavioral Sciences 12/2011; 12:290-299. DOI:10.1016/j.sbspro.2011.02.038
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mediator (MED) is a fundamental component of the RNA polymerase II-mediated transcription machinery. This multiprotein complex plays a pivotal role in the regulation of eukaryotic mRNA synthesis. The yeast Mediator complex consists of 26 different subunits. Recent studies indicate additional pathogenic roles for Mediator, for example during transcription elongation and non-coding RNA production. Mediator subunits have been emerging also to have pathophysiological roles suggesting MED-dependent therapeutic targets involving in several diseases, such as cancer, cardiovascular disease (CVD), metabolic and neurological disorders.
    Biochimie 03/2012; 94(3):579-87. DOI:10.1016/j.biochi.2011.09.016 · 3.12 Impact Factor
Show more