Vitamin heterodimerizes

The retinoid X receptor (RXR) is a nuclear receptor that binds and is activated by certain endogenous retinoids, such as 9-cis-retinoic acid. RXR is the obligatory heterodimerization partner for a large number of nonclassic steroid nuclear receptors, such as thyroid hoimone receptor, vitamin D3 receptor, peroxisome proliferator-activated receptor and pregnane X receptor. 

Vitamin A has a very important role in regulating the actions of other hormone- and nutrient-dependent genes because the RXRs can interact with other nuclear receptors to form heterodimers that are able to bind and regulate hormone and nutrient responsiveness. The RXRs are able to heterodimerize with the vitamin D receptor, the thyroid hormone receptors, the peroxisome proliferator activated... 

Retinoids (e.g. retinoic acid) are involved in development and in metabolic regulation (e.g. through induction of expression of PEPCK, the rate limiting enzyme in gluconeogenesis). Retinoic acid derives from retinol, which in turn derives from ingestion of plant a-, 3- and "/-carotenes and other carotenes. Retinoic acid acts via retinoic acid receptors and retinoid X receptors note that these receptors can heterodimerize in the nucleus with other related hormone receptors such as PPA-Rs. The developmental importance of retinoic acid is underscored by the teratogenicity of retinoic acid and other vitamin A related compounds, notably some compounds developed for anti-acne properties. 

Retinoic acid modulates gene expression and tissue differentiation, acting by way of nuclear receptors. Historically, there was confusion between the effects of deficiency of vitamins A and D by the 1950s, it was believed that the confusion had been resolved. Elucidation of the nuclear actions of the two vitamins has shown that, in many systems, the two act in concert, forming retinoid-vitamin D heterodimeric receptors hypervitaminosis A can antagonize the actions of vitamin D. 

A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes and Development, 9, 769-782. 

A FIGURE 11-42 Consensus sequences of DNA response elements that bind three nuclear receptors. The response elements for the glucocorticoid receptor (GRE) and estrogen receptor (ERE) contain inverted repeats that bind these homodimeric proteins. The response elements for heterodimeric receptors contain a common direct repeat separated by three to five base pairs, for the vitamin D3 receptor (VDRE), thyroid hormone receptor (TRE), and retinoic acid receptor (RARE). The repeat sequences are indicated by red arrows. [See K. Umesono etal., 1991, Ce//65 1255, and A. M. Naaretal., 1991, Ce//65 1267]... 

The active form of vitamin D, 1,25 dihydroxy-vitamin D (l,25(OH)2D), binds to the vitamin D receptor (VDR), which is expressed in most cells. l,25(OH)2D functions as a steroid hormone, usually by heterodimerization with the retinoid X receptor, binding to vitamin-D response elements (VDRE) located in promoter regions. It induces the expression of target genes involved in many cellular responses, including the immune responses. 

Schrader M, Muller KM, Becker-Andre M, Carlberg C (1994) Response element selectivity for heterodimerization of vitamin D receptors with retinoic acid and retinoid X receptors. J Mol Endocrinol 12 327-339... 

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]. 

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