Vitamin receptor dimers

The vitamin D receptor- RXR heterodimer binds in 5 RXR-VDR3 polarity to a direct repeat hormone response element However, the vitamin D receptor also forms heterodimers with the retinoic acid receptor and the thyroid hormone receptor. All three vitamin D receptor dimers can interact with either direct repeat or inverted palindromic hormone response elements. In heterodimers, the vitamin D receptor may be at the 5 -position or 3 -position, resulting in six types of activated vitamin D receptor dimers that can bind to two types of response elements, raising the possibility of multiple signaling pathways (Carlberg, 1996 Carlberg et al., 2001 Yamada et al., 2001b). 

The retinoid receptors function as dimers. Thus, the RAR subtypes heterodimerize with the RXR subtypes. The RXRs also can homodimerize or heterodimerize with the vitamin D, thyroid hormone, and the orphan receptors. The receptor dimers act either directly or indirectly to regulate gene function. The dimers bind directly to retinoid response elements (RAREs and RXREs). These response elements (REs) are specific sequences in the promoter regions of retinoid-responsive genes, which typically consist of two conserved sequences of six nucleotide bases that are separated by discrete numbers of bases. For example, RXR-RAR dimers bind to RAREs which are direct repeats of AGGTCA separated by five (synthetic DR-5 sequence) or two (synthetic DR-2) nucleotides or are palindromic, inverted, or more complex in structure [6]. 

Forms a dimer with the retinoic acid receptor or vitamin D receptor. 

The vitamin D receptor acts mainly as a heterodimer with the retinoid X receptor (RXR Section 2.3.2.1). Binding of calcitriol induces a conformational change in the receptor protein, permitting dimerization with occupied or unoccupied RXR, followed by phosphorylation to activate binding to the vitamin D response element on DNA (DeLuca and Zierold, 1998). Abnormally high concentrations of 9-cis-retinoic acid result in sequestration of RXR as the homodimers, meaning that it is unavailable to form heterodimers with the vitamin D receptor (or other receptors) excessive vitamin A can therefore antagonize the nuclear actions of vitamin D (Haussler et al., 1995 Rohde et al., 1999). 

These retinoid receptors must form dimers before they interact with RAREs. RARs must form heterodimers with RXR.S, whereas RXRs may also form homodimers. It appears that the RAREs for the homodimers differ from those for the heterodimers. This implies that they may activate different sets of genes. RXRs also form hetcrodimers with thyroid hormone receptors and vitamin O receptois. increasing their affinity for DNA. Several enzymes whose expression depends on RXR have been found. The available experimental data provide convincing evidence that these proteins are, in fact, nuclear receptors belonging to the steroid/thyroid hormone superfamily. They mediate important aspects of vitamin A function. The existence of proteins that specifically bind retinoic acid substantiates the implication of retinoic acid as a physiological form of vitamin A. 

Thyroid hormone, 1,25-dihydroxy vitamin D, and retinoic acid receptor regulation of transcription. The hormone receptor (HR) is dimerized at site (3) and is bound to DNA at hormone response element site (2). Without the ligand, transcription is inactive due to the interaction of HR with corepressor at site 4. When the ligand (hormone) binds to HR, the bound corepressor dissociates leading to an interaction between the coactivator and HR. These regulatory changes result in increased transcription. 

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