Retinoic acid-responsive genes

Retinoic acid-responsive genes in which a RARE
has been identifi ed fall into the category of primary
response genes or, in some cases, delayed primary
response genes. These genes, by defi nition, bind
the hormone–receptor complex – in this case, the
RAR–RXR heterodimer – and produce the hormone
responsive protein with no requirement for ongoing
protein synthesis. Primary response genes produce
mRNA within minutes to a few hours after addition of
retinoic acid to cell cultures, whereas delayed primary
response genes produce mRNA only after several
hours. Vitamin A-responsive genes, which apparently
have no RARE and which produce mRNA only after
several hours, are categorized as secondary response
genes. These genes, by defi nition do not bind the hormone–
receptor complex. They may be regulated by a
transcription factor produced by a primary response
gene or they may be regulated at the post-transcriptional
level. In the latter case, for example, retinol acts
by stabilizing newly synthesized alkaline phosphatase
transcripts (Zhou et al., 1994), regulating the processing
of interleukin-1 precursor transcripts into mature
mRNA (Jarrous & Kaempfer, 1994) and increasing
the half-life of connexin43 by inducing adhesion
molecules (Bex et al., 1995).
The many retinoic acid-responsive genes encode
proteins having very diverse functions. The proteins
include nuclear retinoid receptors, cellular retinoidbinding
proteins, transcription factors, enzymes, extracellular
matrix proteins and growth factors (Table
7.4). The RAREs that are present in primary response
genes frequently consist of direct repeats of two core
recognition motifs with consensus sequence AGGTCA
separated by 5, 2 or 1 base pairs and designated
DR5, DR2 and DR1 elements, respectively. Sequence
differences from the consensus do occur and generally
result in a reduced transcriptional response to retinoic
acid owing to a lower receptor binding affi nity. RAREs
are not exclusively of the direct repeat type: everted
repeat elements were identifi ed in the genes encoding
γF-crystallin (Tini et al., 1993) and medium-chain
acyl-coenzyme A dehydrogenase (Raisher et al.,
1992). In the latter gene, the response element was
activated by RXRα in preference to RARα or RARβ
and thus could be described as an RXRE.
The promoters of some genes contain composite
response elements which can selectively bind and
initiate transcription from multiple nuclear hormone
receptors, thereby allowing cross-talk between different
hormonal pathways. For example, the rat oxytocin
promoter contains a RARE that is predominantly
responsive to retinoic acid, but also permits binding
of TR and ER (oestrogen receptor) to mediate
transcription in the presence of thyroid hormone
and oestradiol (Adan et al., 1993). Kato et al. (1995)
described a novel class of response elements which are
widely spaced (10 to 200 base pairs) direct repeats of
the consensus AGGTCA motif (DR10 to DR200) and
which act as promiscuous transactivation sites for ER,
RAR–RXR and VDR–RXR, but not TR–RXR.
In the following discussion, special attention is given
to the genes encoding the retinoid receptors and the
cellular retinoid-binding proteins, as these proteins
are physiologically important in vitamin A function.
Also discussed are the homeobox and oct genes, which
are involved in embryonic development.