ControlofGeneExpressionbyVitaminDReceptor

The vitamin D receptor, VDR is the mediator of all genomic actions of vitamin D3 and its analogs. It belongs to a family of ligand induced transcription factors, nuclear receptors (NRs). Vitamin D3 is the main regulator of calcium homeostasis and is critical in bone formation. It is also involved in controlling cellular growth, differentiation and apoptosis, which makes synthetic vitamin D3 analogues interesting for therapy of such diseases as cancer and psoriasis. NRs are comprised of: an amino-terminal activation function domain AF-1; the DNA-binding domain; a hinge region; and a carboxy-terminal ligand-binding domain containing a second activation function, AF-2. VDR acts primarily as a heterodimer with the retinoid X receptor (RXR) on vitamin D response elements (VDREs). It interacts with the transcription machinery and nuclear receptor coactivators or corepressors to regulate target gene activity. NR’s coregulators can be divided into 3 major classes: 1)ATP-dependent chromatin remodeling complexes that are involved in the location and association of nucleosomes with DNA; 2) Enzymes that catalyze modifications of histone tails to regulate histone-histone and histone-DNA interactions 3) General transcription factors adaptors that bridge the functions between regulators and basal transcription factors. A novel multifunctional ATP-dependent chromatin remodeling complex c WINAC directly interacts with the vitamin D receptor. It contains BRG1 or hBRM as ATPase subunits as all SWI/SNF complexes do, but it also has subunits associated with DNA replication (TopoII_ and CAF-1p150) and transcript elongation through nucleosomes (FACTP140) not found before in SWI/SNF complexes. WINAC also contains the Williams syndrome transcription factor (WSTF). WSTF appears to function as a platform protein for the assembly of components in WINAC, and it interacts directly with the vitamin D receptor in a ligand-independent manner. WINAC and vitamin Dreceptor are targeted to vitamin D responsive promoters in the absence of ligand to both positively and negatively regulated genes. WINAC may rearrange the nucleosome array around the positive and negative VDREs, thereby facilitating the coregulatory complexes access for further transcription control. Upon ligand binding, two HAT complexes, p160/CBP and TRRAP/PCAF, coactivate the NR function. The p160 proteins (SRC protein family) interact directly with an NR activation surface AF2 and serve as platforms for the recruitment of histone-modifying enzymes, including CBP/p300 and methyltransferases. The SRC/p160 family members SRC-1 and p/CIP, as well as CBP and p300 contain intrinsic histone acetyltransferase activity(HAT). Both the HAT activity and the histone methyltransferase activity may cooperate in histone modification and facilitate nucleosome remodeling and recruitment of transcriptional machinery. A third group of coactivators is represented by thyroid receptor-associated proteins (TRAP)/vitamin D receptor-interacting proteins (DRIP). This complex may play a role by directly contacting the basal transcriptional machinery. As the VDR/RXR heterodimer also represses transcription in a ligand-dependent manner through negative VDRE (nVDRE), a number of corepressor proteins such as NCoR and ALIEN may also be recruited to the surface of the receptor. They, too function as platforms but serve to recruit enzymes such as histone deacetylases. WINAC association with VDR facilitates targeting of a putative corepressor complex to the nVDRE

Contributor: A. Konev, PhD

REFERENCES: Belandia B, Parker MG. Nuclear receptors: a rendezvous for chromatin remodeling factors. Cell. 2003; 114(3):277-80. Kitagawa H et al. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome.Cell. 2003;113(7):905-17. McKenna NJ et al. Nuclear receptor coregulators: cellular and molecular biology.. Endocr Rev. 1999;20(3):321-44. McKenna NJ, O'Malley BW. Minireview: nuclear receptor coactivators--an update. Endocrinology. 2002 Jul;143(7):2461-5.