Please wait while the transcript is being prepared...
0:00
Welcome, everyone,
to Chapter 10 of this
short talk series on
nuclear receptors as
therapeutic targets.
0:10
This chapter will address
the retinoic acid receptors,
which exist in three subtypes,
RAR-alpha, beta, and gamma,
and represent the NR1B family.
0:22
The retinoic acid receptors are
closely linked to vitamin A
and bind the vitamin A metabolite
all-trans retinoic acid
as a natural ligand.
For this, the provitamin
beta-carotene
is oxidatively
cleaved to retinal,
which is essential for
vision and other processes.
Retinal is further
oxidized to retinoic acid,
which exists in a
number of isomers.
The all-trans retinoic acid,
often abbreviated as ATRA,
is the natural agonist of
retinoic acid receptors,
while the 9-cis retinoic acid,
and, likely also,
other related species,
are natural retinoid
X receptor ligands.
As RAR typically acts as
a heterodimer with RXR,
also the 9-cis retinoic acid
and related metabolites
are relevant to RAR activity.
1:14
The RAR-RXR heterodimer
is DNA-bound also
in the absence of a ligand,
recruits corepressors,
and thus can act as a
transcriptional repressor.
Agonist binding,
for example all-trans
retinoic acid,
leads to corepressor release
and coactivator recruitment
to enable transcription.
With both the repressor
and transcriptional
activator activity,
RAR involves in many
physiological processes.
RAR activity is essential
for development of many organs
and also has a role in
regulating cell differentiation
and apoptosis.
RAR activation can induce
terminal differentiation
of certain cancer cells,
and there are mutant
RAR forms that act as
overactive repressors
in some cancers.
RAR agonism, thus, has
potential in cancer treatment.
Additionally, RAR
participates in
the transcriptional regulation
of cancer resistance factors,
like drug transporters,
and RAR is also involved
in the regulation
of hematopoietic stem
cells and immune cells.
Lastly, it has an
important role in the skin
by controlling keratinocyte
proliferation,
epidermal cell turnover,
and collagen production.
