RETRACTED: Multiple co-activator complexes support ligand-induced transactivation function of VDR

DDX5 is a multifunctional co-activator of steroid hormone receptors

“…Thus, the precise role of DDX5 in stimulating vitamin D-regulated transcription remains to be determined. Owing to its ability to interact with several components of the transcriptional machinery (e.g., CBP and p300, both of which also associate with VDR; RNA polymerase II; HDAC1) as well as with the splicesome component U1 snRNA (Jacobs et al, 2007;Metivier et al, 2003;Rachez and Freedman, 2000;Rossow and Janknecht, 2003;Wilson et al, 2004;Yamaoka et al, 2007), it is tempting to speculate that DDX5 might serve as an adaptor molecule or bridging factor that not only facilitates the formation of transcriptional initiation complexes by recruiting specific components of the transcription machinery (including chromatin remodeling factors) but may also serve to coordinate transcription with the post-transcriptional process, hence improving the kinetics of production of mature mRNA (Auboeuf et al, 2002(Auboeuf et al, , 2005Clark et al, 2008b;Fuller-Pace, 2006;Fuller-Pace and Ali, 2008), a concept consistent with current models of gene expression (Ares and Proudfoot, 2005;Proudfoot et al, 2002). In analogy with the suggestion of MacDonald et al (2004)), who proposed a pivotal role for SKIP/NCoA-62 as a transcription/splicing coupling factor based on their observations (i) that endogenous SKIP is recruited to native VDR-responsive promoters in a calcitriol-dependent manner in osteoblast cells where it cooperatively associates with the transcriptional machinery and (ii) that SKIP is furthermore present in nuclear spliceosome complexes, we propose that DDX5 may be a novel VDR interactor in human keratinocytes, having dual roles in transcriptional co-activation and transcript processing to yield mature calcitriol-responsive target-gene mRNAs.…”

Vitamin D and MicroRNAs in Bone

“…58 In view of the proposed role for vitamin D in protecting against autoimmunity, 59 it is tempting to speculate that miR-326 may act to impede the postulated immunomodulatory effects of 1,25(OH) 2 D in preventing inflammatory, autoimmune activity. Beyond the VDR protein itself, it is important to recognize that VDR responses require specific co-regulators that direct 1,25(OH) 2 D-mediated expression of target genes, 47,49,60,61 and these accessory proteins are also likely to be regulated by miRNAs. Targeting of NR co-regulatory proteins by miRNAs has been described previously, 27,28 and specific miRNAs have been predicted to affect VDR co-activators such as SNW1 (see Table 2).…”

Vitamin D discovery outpaces FDA decision making

“…Although 25-D has some physiologic activity, for example, binding to the vitamin D-binding protein (VDP), and the cartilage oligomeric matrix protein (COMP, see later in this review), it cannot activate the transcriptional activity of the VDR. Another hydroxylation, at the 1-alpha position, is necessary before the ligand-binding pocket (LBP) of the VDR can be constrained (by 1,25-D) into the configuration (14,15) needed for binding the coactivator complexes, (20) allowing the subsequent dimerization to facilitate gene transcription (and repression).…”