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 Nuclear Receptor Activation by Vitamin A

All-trans-retinoic acid (RA), vitamin A, is a pleiotropic factor involved in a wide variety of vertebrate cell processes including embryonic development, morphogenesis, survival, cell growth and differentiation, and tissue homeostasis. The importance of vitamin A is demonstrated by the fact that it is teratogenic when present in excess or deficient levels. Retinol (all-trans-retinol) is converted to retinal (all-trans-retinal) by retinol dehydrogenases (EC 1.1.1.105). All-trans retinal is converted into all-trans-retinoic acid (RA) by retinal dehydrogenases (EC 1.2.1.36).

All-trans-RA is the primary retinoid that affects cell processes at the level of transcription. All-trans-RA is the physiological ligand for a family of nuclear transcription factors, retinoic acid receptors (RAR) that form functional dimers with a second family of nuclear transcription factors, the retinoid X receptors (RXR). RAR and RXR belong to the steroid/thyroid/retinoid nuclear receptor family. RAR is the dominant partner in the RAR:RXR heterodimer. The role of RXR is to synergistically enhance the transcription regulatory effect of RAR. The physiological ligand for the RXR transcription factors is thought to be 9-cis-retinoic acid, but this is not definitively established. RAR:RXR heterodimers bind to DNA via cognate recognition sequences and mediate or modify gene expression through complex context and cell-specific interactions with transcription machinery.

There are three known RAR isotypes, RARα, RARβ, and RARγ that have been found as a variety of isoforms, RARα1, RARα2, RARβ1/β3, RARβ2/β4, RARγ1, RARγ2. These isotypes result from combinations of gene splicing and alternative promoter initiation events. RXR also exists as three isotypes, RXRα, RXRβ, and RXRγ and various isoforms. The effect of all-trans-RA on a cell’s transcription activity is determined by the specific isotype/isoform combination of RAR and RXR. Together these factors provide an opportunity for a combinatorial number of cell, context and age specific responses to all-trans-RA.