Retinoic acid and its relatives, natural products of vitamin A metabolism,
have been discovered to be critical ligands for key receptors of the steroid
receptor superfamily, such as the retinoic acid receptor and the RXR receptor.
Vitamins and Hormones has not had a review of this important fatsoluble
vitamin for some time, and it seemed important not only to touch on
the modern aspects of the retinoic acid receptor and its relatives but also of
the roles of vitamin A in development and diVerentiation as well as its
activity in certain tissues and in disease states....
Retinoic acid receptor (RAR) and retinoid X receptor are ligand-induced
transcription factors that belong to the nuclear receptor family. The
receptors are activated by small hydrophobic compounds, such as
all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Interestingly,
these receptors are also targets for a number of exogenous compounds.
A pair of nuclear receptors, ecdysone receptor (EcR) and ultraspiracle
(USP), heterodimerize and transduce ecdysteroid signals. The EcR and its
nonsteroidal ligands are being developed for regulation of transgene expres-sion in humans, animals and plants. In mammalian cells, EcR:USP
heterodimers can function in the absence of ligand, but EcR⁄retinoid X
receptor (EcR:RXR) heterodimers require the presence of ligand for activa-tion.
Analyses of integration of two-hormone signaling through the vertebrate
nuclear hormone receptors, for which the retinoid X receptor is one part-ner, have generated a number of mechanistic models, including those des-cribed as ‘subordination’ models wherein ligand-activation of one partner
is subordinate to the liganded state of the other partner.
Alcohol dehydrogenase (ADH) deficiency results in
decreased retinol utilization, but it is unclear what physio-logical roles the several known ADHs play in retinoid
signaling. Here, Adh1, Adh3,andAdh4null mutant mice
have been examined following acute and chronic vitamin A
excess. Following an acute dose of retinol (50 mgÆkg
metabolism of retinol to retinoic acid in liver was reduced
10-fold inAdh1mutants and 3.8-fold inAdh3mutants, but
was not significantly reduced inAdh4mutants.
Retinoid receptors are ligand-dependent transcription
factors belonging to the nuclear receptor superfamily.
Retinoic acid (RARa, b, c) and retinoid X (RXRa, b, c)
receptors mediate the retinoid/rexinoid signal to the
transcriptional machineries by interacting at the first level
with coactivators or corepressors, which leads to the
recruitment of enzymatically active noncovalent com-plexes at target gene promoters.