Current Medicinal Chemistry, 2011, 18, 1405-1412 1405

Regulation of Gene Expression by Retinoids

P.M. Amann1,2, S.B. Eichmller1,2, J. Schmidt3 and A.V. Bazhin*,1,2,3
1
Skin Cancer Unit, German Cancer Research Center Heidelberg, Germany
2
Department of Dermatology, University Hospital Mannheim, Germany
3
Department of Surgery, University Hospital Heidelberg, University of Heidelberg, Germany
Abstract: Vitamin A serves as substrate for the biosynthesis of several derivates (retinoids) which are important for cell growth and cell
differentiation as well as for vision. Retinoic acid is the major physiologically active form of vitamin A regulating the expression of dif-
ferent genes. At present, hundreds of genes are known to be regulated by retinoic acid. This regulation is very complex and is, in turn,
regulated on many levels. To date, two families of retinoid nuclear receptors have been identified: retinoic acid receptors and retinoid X
receptors, which are members of the steroid hormone receptor superfamily of ligand-activated transcription factors. In order to regulate
gene expression, all-trans retinal needs to be oxidized to retinoic acid. All-trans retinal, in turn, can be produced during oxidation of all-
trans retinol or in a retinol-independent metabolic pathway through cleavage of
-carotene with all-trans retinal as an intermediate me-
tabolite. Recently it has been shown that not only retinoic acid is an active form of vitamin A, but also that all-trans retinal can play an
important role in gene regulation. In this review we comprehensively summarize recent literature on regulation of gene expression by
retinoids, biochemistry of retinoid receptors, and molecular mechanisms of retinoid-mediated effects on gene regulation.
Keywords: Retinoic acid, retinol, retinal, retinoic acid receptor, gene expression.

INTRODUCTION
Two important physiological roles are assigned to vitamin A:
participation in the visual cascade [1] and regulation of growth and
development [2]. For a long time it has been known, especially in
skin, that retinoids, particularly retinoic acid, have critical regula-
tory functions, [3] and appear to modulate tumor development and
progression. All-trans retinoic acid is the major physiologically
active form of vitamin A, regulating the expression of different
genes both in the embryo and in the adult organism [4]. In 1912
Funk suggested the term vitamin as a growth factor essential for
life present in food [5]. The discovery of vitamin A traces back to
1906, showing that factors other than proteins, carbohydrates, and
fats are necessary for night vision (for review of the history of vi-
tamin A discovery see [6]). The isolation of a fat-soluble factor
important for the rat diet was reported at the beginning of the 20th
century [7]. Since a water-soluble factor B (vitamin B) had been
discovered, this fat-soluble factor was christened as vitamin A. The
next important step was the first chemical synthesis of this vitamin
in 1947 [8], allowing the first large scale pharmaceutical produc-
tion. Mammals cannot synthesize vitamin A active compounds,
therefore the necessary quantities are obtained by ingestion of vita-
min A (retinol and retinyl ester) or by consumption of appropriate
provitamin A compounds, such as
-carotene. The natural retinoids
found in food are mainly retinyl ester found in animal fat and
-
carotene in vegetables (e.g. carrots, pumpkin, cabbage and spinach)
[9]. Malnutrition can lead to vitamin A deficiency, which is mani-
fested by blindness, prenatal developmental dysfunctions and
weakness of the immune system. The IUPAC-IUB Joint Commis-
sion on Biochemical Nomenclature (Recommendations 1981) rec-
ommends that the term vitamin A should be used as the generic
descriptor for retinoids exhibiting qualitatively the biological activ-
ity of retinol [10].
8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,
8-tetraen-1-ol), retinal or retinaldehyde (RAL, an aldehyde derivate
of vitamin A), and retinoic acid (RA) are the most characteristic
examples of naturally occurring retinoids (Fig. 1). Their structure is
generally divided into three segments: a hydrophobic
-ionone ring,
a conjugated tetraene side chain and a polar terminal group. Such
structure predisposes a large sensitivity of retinoids to light, mani-
festing in a photoisomerisation, leading finally to their degradation
[11]. At present there are a number of chemical modification ap-
proaches used to create stable retinoid derivates [12-14]. Retinoids
are also excellent chromophores which efficiently absorb light in
the region of 300400 nm, depending on the solvent [15]. Natural
vitamin A modifications include (i) a change of the functional
group (retinyl esters, retinal oximes and others), (ii) hydrogenation
(dehydroretinol and others), (iii) eliminations of CH3, CH2, CH or C
group (motrenide and others), (iv) shifting of the conjugated
polyene system by one position of the conjugated polyene system
(anhydro-vitamin A) and other modifications. The absolute stereoi-
somery at chiral centres of retinoids can be in R or S configuration.
Both cis and trans stereoisomers of retinoids exist [16].
OH
all-trans retinol
O
all-trans retinal

VITAMIN A AND ITS DERIVATES

OH
Retinoids are a class of biochemical compounds consisting of
four isoprenoid units which are joined in a head-to-tail manner. A O
chemical base of a retinoid is a monocyclic compound containing all-trans retinoic acid
five carbon-carbon double bonds and a functional group at the ter-
minal acyclic tail. The three retinoids: retinol (ROL, (2E, 4E, 6E, Fig. (1). Molecular structure of ROL, RAL and RA.

The chemical structure of
-carotene consists of eight isopre-

*Address correspondence to this author at the Department of Surgery, University noid units which can be cleaved in the organism by carotenoid di-
Hospital Heidelberg, Im Neuenheimer Feld 350, D-69120 Heidelberg, Germany; Tel: oxygenase mostly at the central C15-C15' double bond. Cleavage of
+49-6221-5636932; Fax: +49-6221-568240;
E-mail: alexandr.bazhin@med.uni-heidelberg.de other double bonds gives
-apo-carotenals, which can be further

0929-8673/11 $58.00+.00 2011 Bentham Science Publishers Ltd.

1406 Current Medicinal Chemistry, 2011 Vol. 18, No. 9
oxidized to RAL and reduced by retinal reductase to ROL [17].
More then 400 natural carotenoids are known, but only 50-60 of
them have provitamin A activity, which means that they can be
converted to vitamin A [9].
GENE REGULATION MEDIATED BY RETINOIC ACID
Retinoids can be also classified as hormones, like steroid and
thyroid hormones. RA mediates its function normally through the
specific retinoid receptors, which belong to the ligand-dependent
transcription factors superfamily of nuclear receptors [18]. Fur-
thermore, non-receptor-depended effects of retinoids are also
known.
Retinoid Receptors
At present, hundreds of genes are known to be regulated by RA
[19-21]. This regulation is very complex and is, in turn, regulated
on many levels. Physiological effects of retinoids are mainly medi-
ated by two families of nuclear receptors, which influence gene
transcription [22]: (i) retinoic acid receptors (RAR) [23, 24], and
(ii) retinoid X receptors (RXR) [25]. RAR and RXR belong to the
nuclear hormone receptor superfamily [26] and are ligand-
dependent transcription factors. Several isotypes of RAR and RXR
have been identified: RAR-
, RAR-, RAR- and RXR-
RXR-,
RXR-. Each of these receptors is encoded by a distinct gene [27,
28]. Such multiplicity of the receptor isoforms has benefit for better
regulation of their activity. Three of the retinoid receptors (RAR-
,
AF-1 Hinge
N A/B C D
DBD
RAR DBD
Zn
Zn
Fig. (2). Retinoid receptor: (A). Schematic presentation of the functional domains of retinoid receptors; (B). Three-dimensional structure of the RXR-RAR
DNA-binding domain (DBD) on the RARE DR1 (adapted from the protein Data Bank; see [83]).
Amann et al.
RXR-
and RXR-) are ubiquitously expressed, while the others
have tissue-specific expressions [29]. The
-, - and -isotype of
RAR can be bound and activated by all-trans RA as well as by 9-cis
RA. However, RXR-
, - and - are primarily activated by 9-cis
RA [30-32]. By binding of retinoids, nuclear receptors are activated
and hetero- or homodimerize (RAR/RAR and RAR/RXR) [33].
Moreover, RXR is able to heterodimerize with other receptors like
the vitamin D3-receptor (VDR), thyroid hormone receptor (TR),
peroxisome proliferator-activator receptor (PPAR) and orphan re-
ceptors [34-36]. However, under physiological conditions it is sup-
posed that retinoids influence gene transcription mainly by forma-
tion of RAR/RXR-complexes [37, 38].
Retinoic acid receptors consist of six domains, termed A-F,
with independent functions (Fig. 2A). The amino terminal A/B
domains have an activity of ligand-independent transactivation
(AF-1). This domain contains several phosphorylation consensus
sites for cyclin-dependent- and MAP kinases [39]. The highly con-
served domain C functions as the DNA-binding domain, composed
of two zinc fingers, two
-helices and a COOH-terminal extension
forming the core of the domain (Fig. 2B). Sequence of the first zinc
finger is responsible for discriminating DNA sequences. The sec-
ond zinc finger is involved in receptor dimerization [40]. The D
region is a hinge between the DNA-binding and ligand-binding
domains, facilitating the steric conformation of the DNA-binding
domain [41]. Besides this function, this domain is probably respon-
sible for the interaction with transcriptional coregulators, and has,
therefore, a nuclear localization signal in its sequence [42]. Ligand-
binding domain (E) is the second highly conserved multifunctional
AF-2
E F C
LBD
RXR DBD
Zn
Zn
DNA (DR1)
Gene Expression and Retinoids
Table 1. DR Sequences for Nuclear Receptor Dimers
DR Sequence Receptor dimerisation
AGGTCAnAGGTCA
DR1
TCCAGTnTCCAGT
AGGTCAnnAGGTCA
DR2
TCCAGTnnTCCAGT
AGGTCAnnnAGGTCA
DR3
TCCAGTnnnTCCAGT
AGGTCAnnnnAGGTCA
DR4
TCCAGTnnnnTCCAGT
AGGTCAnnnnnAGGTCA
DR5
TCCAGTnnnnnTCCAGT
domain complex, consisting of (i) the ligand pocket, (ii) the main
dimerization domain and (iii) the ligand-dependent transactivation
function domain (AF-2) [43]. Several ligand-binding crystal struc-
tures of different nuclear receptors, including RAR and RXR, have
been solved [44]. These investigations have shown a helical sand-
wich fold in the ligand-binding domain, whose conformation
changes upon ligand binding. X-ray analysis has determined a con-
formational change between an open apo-form and a compact
closed holo-form after ligand binding [44]. Interesting to note, this
domain also contains phosphorylation sites which serve as targets
for protein kinase A and MAP kinases [45]. The F domain is pre-
sent only in RAR, but not in RXR, and the putative role of this
domain is not yet understood. It was supposed that this region may
be involved in modulation of the activation functions of AF-1 and
AF-2 [46].
Retinoic Acid Response Elements
The next level of complexity is the interaction of the retinoid
nuclear receptors with a specific element found in many different
promoters, the retinoic acid response element (RARE), that matches
or relates closely to the sequence AGGTCA [25]. These elements
are located in the promoter or enhancer regions of specific target
genes [22]. The recognition of the RARE relies on the cooperative
assembly of RAR-RXR heterodimers onto DNA, or isolated RAR
and RXR [41]. In addition, direct repeats (DR) of RARE with a
spacer of two to five nucleotides (DR2-DR5), are known to be in-
volved in the binding with homodimers of RXR, which is the com-
binatorial partner in the nuclear receptor family [47]. The dimeriza-
tion partners of RXR can be RXR itself (for DR1), RAR (for DR1,
DR2 and DR5), VDR (for DR3), PPAR (for DR1) and other recep-
tors (Table 1). The number of combinatorial interaction of these
receptors can be enlarged by changing their polarity on a DR, bind-
ing alternatively to the upstream or downstream in some DR. Such
polarity reversion is important for switching the activity of the re-
ceptor heterodimer from an activator to a repressor of retinoid re-
sponsive genes [28].
Molecular Mechanism of Gene Regulation by Retinoic Acid
Physiological actions of retinoids are manifestated in
RAR/RXR-mediated transactivation or transrepression [48]. The
retinoic acid-mediated transactivation is believed to be realized in
several steps: (i) ligand binding, (ii) dimerization, (iii) interaction
with DNA, (iv) recruitment of coactivators and (v) finally RNA
elongation. The current model of gene regulation by retinoids has
been proposed by Dilworth et al. [49]. In the absence of ligand,
Current Medicinal Chemistry, 2011 Vol. 18, No. 9 1407
References
RAR/RXR [84]
RXR/RXR [85]
RXR/COUP [86]
RXR/HNF4 [87]
RXR/PPAR [88]
RAR/RXR [84]
RXR/PPAR [88]
RXR/VDR [89]
RXR/CAR [90]
RXR/LXR [91]
RXR/TR [92]
RAR/RXR [84]
RXR/NGFI-B [93]
retinoid receptors are bound to RARE, located in the promoter of
target genes which are associated with histone deacetylase-
containing complexes (Fig. 3). These complexes recruit the corep-
ressors N-CoR and SMRT leading to the repression of transcription
[50]. Conformational changes in the receptors upon ligand binding
lead to the dissociation of corepressors and to the recruitment of
coactivators which form an activating complex, including histone
acetyltransferase (HAT), methyltransferase (MTA) and kinases [43,
44]. Coactivators have in their sequences a leucine-rich LXXLL
signature motive [51]. Corepressors possess a related L/IXXI/VI
motif [52]. The main coregulators of ligand-recruited retinoid re-
ceptors are listed in Table 2. Interestingly, some coactivators have
domains which take part in the interaction with other coactivators,
showing a cooperativeness of the coactivator recruitment by the
receptors [53]. Finally, chromatin is decondensed, subsequently the
p160 coactivators dissociate and the retinoid receptors become
capable of recruiting the transcriptional machinery, including RNA-
Pol II and general transcription factors which in turn increase
chromatin remodeling at the promoter regions [54, 55] (Fig. 3).
Regulation of RAR/RXR-Mediated Effects
Proteasomal degradation and phosphorylation are important
mechanisms in retinoid-mediated gene regulation. It was shown that
ubiquitinylated RAR/RXR heterodimers bound to RARE can be
degraded by the proteasome after retinoids binding [56, 57]. The
degradation processes can provide a control mechanism for the
extension and duration of retinoid-mediated regulation of gene
expression. As mentioned before, RAR are substrates for different
classes of kinases. It has been proposed that phosphorylation can
facilitate the recruitment of molecular components of transcription
[39]. In addition, the phosphorylation of corepressors leads to inhi-
bition of their interaction with the receptors [58].
Another mechanism modulating retinoid-mediated gene regula-
tion, so-called transrepression, is characterized by the ability of RA
to down-regulate AP1 activity [59]. AP1 (activator protein 1) is also
an important transcription factor for many genes, and is composed,
in one case, of the c-jun and c-fos proteins. It has been proposed
that direct or indirect protein-protein interactions between AP1 and
the RA receptor are responsible for the mechanism of transrepres-
sion [60]. Transrepression seems to be a basic mechanism of phar-
macological, anti-inflammatory and anti-proliferative effects of
retinoids [37].
The retinoid-mediated effects can be negatively regulated by
certain orphan receptors such as TAK1 or TR4 and chicken oval-
bumin upstream promoter-transcription factor (COUP-TF) [61, 62].
1408 Current Medicinal Chemistry, 2011 Vol. 18, No. 9 Amann et al.

HDAC
RNA pol II
N-CoR/SMRT -

Histone
deacetylation

RARE
Gene silencing

RA + - RA

HAT
Kinases MTA +

Chromatin
decondensation RNA pol II
RARE
RNA
Gene activation
Recruitment of the
transcriptional machinery

Fig. (3). Simplified schema of the mechanism of retinoid receptor action. For details see text and Table 2.

Table 2. The Main Coregulator of Ligand-Recruited Retinoid Receptors

Coregulator family Members Main features References

Coactivator SRC SRC-1, TIFII, GRIP1, p160, RAC3, Intrinsic HAT activity, acetylation of histones [94]
ACTR, p/CIP, AIB-1 [95]
p300 cAMP responsive activity [96]
CBP HAT activity [97]
P/CAF Intrinsic HAT activity [97]
Interaction with basal transcription factor TFIIB [98]
GRIP, TIF2, p160 Autonomous transcription activity [99]
[100]
TIF1 Enhancing of AF-2 mediated activation [101]
TRIP1, SUG1 Enhancing of phosphorylation of RNA-Pol II [102]
SW1, SNF Mediating of ATP-dependent disruption of [103]
nucleosomes
PGC-1 Coactivation of transcription factor HNF-4
[104]
Bifunctional transcriptional NSD1 Separate activation and repression functions [105]
intermediary factors FKHR [106]
CRABPs CRABPI and Facilitating the formation of holo-receptors [107]
CRABPII
ASC-2 CBP recruiting [108]
CARM1 Nucleosome methylation [109]
Corepressor SMRT, N-CoR Forming the repressive complex with HDAC* [110]
RIP140(NRIP1) [111]
PSF [112]
SUN-CoR Interaction with SMRT and N-CoR [113]
TRUP Interference with DNA binding [114]

*HDAC histone deacetylase.

Gene Expression and Retinoids
Epigenetic effects through
postranslational modifications and
cross-talk with different receptors
RA ROL
Vision
11-cis RAL as ligand
for visual opsin
Fig. (4). Schematic summation of the main receptor and non-receptor effects of retinoids.
TAK1 does not form a heterodimer with RAR or RXR, but the
homodimers of TAK1 compete with RAR/RXR heterodimers for
binding to RARE [61]. COUP-TF competes not only with
RAR/RXR but also with other receptors such as PPAR, VDR and
TR [62]. Thus, regulation of the retinoid-mediated effects is rather
complex, involving different molecular and biochemical mecha-
nism resulting in a fine-tuning mechanism for gene regulation by
retinoids.
Involvement of Retinoid-Mediated Regulation of Gene Expres-
sion in Other Signaling Pathways and Non-Receptor-Dependent
Effects of Retinoids
RAR is able to interact with multiple coactivator and corepres-
sor proteins, similar to other nuclear receptors, changing the epige-
netic status of regulatory domains of target genes [22]. In this con-
text it has to be mentioned that RA can induce cell cycle arrest. The
influence of retinoids on expression of key regulators and their
posttranslational protein stability has been described in several cell
types [63, 64].
As such, RAR
and RAR are critical regulators of prolifera-
tion and cell growth inhibition [22]. It has been showed that RAR-
2 controls the amount of the important cell cycle regulators
p21CIP1 and p27KIP1, which are inhibitors of cyclin-dependent
kinases (CdK) [65]. Another way that RA modulates the cell cycle
is to increase the proteolytic turnover rate of the key cell cycle pro-
teins regulators, cyclin D1, D3 [38] and cyclin E [22]. Retinoid-
mediated signaling is involved in cross-talk with c-myc, interferons,
tumor-necrosis factor and other growth regulatory pathways [66-
68]. Moreover, retinoids play an important role in the regulation of
apoptosis in normal development and in disease [69].
Interestingly, Cawley et al. have shown that a large number of
non-coding RNAs can be regulated by RA through RAR/RXR [70].
Based on their data, the authors supposed that these non-coding
RNAs could represent simply transcriptional noise.
Furthermore, there is also evidence that the biological effects of
vitamin A derivates do not only occur by RAR/RXR-mediated ef-
fects, but also by non-receptor-dependent effects. For example, in
skin, retinoids have an influence on the activation of signaling
pathways as a response to UV-light [71]. In addition, ROL and RA
are able to bind the enzyme c-RAF directly. By modulating the UV-
induced enzyme activity, ROL has influence on gene regulation via
the c-RAF/MAPK-pathway [72]. Also, a recently published study
in epidermal keratinocytes has shown that RA regulates cell prolif-
eration and hyaluronate production, via a fast non-genomic mecha-
nism, by epidermal growth factor receptor signaling [73]. The main
Current Medicinal Chemistry, 2011 Vol. 18, No. 9 1409
Regulation of gene expression
through RAR, RXR, PPAR, COUP,
HNF4, VDR, CAR, LXR,
TR and NGFI-B
RAL
receptor- and non-receptor-mediated retinoid effects are summa-
rized in Fig. (4).
GENE REGULATION BY RETINOIDS DIFFERENT FROM
RETINOIC ACID
Recently it has been shown that not only RA is an active form
of vitamin A, also RAL can play an important role in gene regula-
tion [74]. In order to regulate gene expression, RAL needs to be
oxidized to RA [75]. RAL in turn can be produced during oxidation
of ROL or in a ROL-independent metabolic pathway through
cleavage of -carotene, with RAL as an intermediate metabolite
[76]. In liver, the storage form of vitamin A is retinyl ester, which
can be hydrolyzed to ROL, with subsequent oxidation to RAL [77].
The important physiological role assigned to RAL is participation
in the visual cascade [1], where 11-cis-RAL serves as a ligand for
visual opsin, playing an essential role in night vision [78]. Cur-
rently, experimental evidence is accumulating assigning RAL other
important functions outside the eye [74, 79].
Duester et al. showed that RAL production is catalyzed by spe-
cifically regulated enzymes, and this process is not tissue-restricted
[79]. Ziouzenkova et al. [74] demonstrated that the enzymes in-
volved in RAL metabolism can be differently regulated during adi-
pogenesis in vivo and in vitro. Besides this, RAL, present in rodent
fat, inhibits adipogenesis and suppresses PPAR and RXR response
[74]. It has been proposed that RAL acts through inhibition the
PPAR/RXR heterodimer by the low affinity binding of RAL to
PPAR. This study allows the attribution of RAL to a gene regula-
tor group, manifesting its activity in a RA-similar manner through
the nuclear receptors.
Can ROL itself be a ligand for retinoic receptors? There is also
evidence that ROL can indeed function as a ligand for the receptors,
binding to RAR
,  and  [80]. The authors found that ROL was
only 4- to 7-fold less potent than RA in binding to RARs [80].
These data would suggest that ROL might also be a potential regu-
lator of gene expression.
The gene regulatory capacity of RA is rather well regulated, be-
cause only one receptor, namely RAR is the specific nuclear recep-
tor for RA [26], and thus the effects of RA on gene regulation can
be fine-tuned. Besides, RAL can be found in mouse fat (0.8 nmol
pro g tissue) [74] and ROL in mouse, rat and human liver (from 1 to
11 mg/g tissue), kidney (0.4-12 mg/g), brain (0.66 mg/g), serum
(about 2.5 mg/g) and testis (0.09 mg/g) [81]. This can be attributed
to important functions of the retinoids different from RA in these
tissues.
1410 Current Medicinal Chemistry, 2011 Vol. 18, No. 9
Summarizing the new findings from the papers cited, it could
be proposed that ROL and RAL, in addition to RA, could be regula-
tors of gene expression, manifesting their effects through the nu-
clear receptors RARs, RXRs and PPAR. This can be important for
the regulation of gene expression in pathological conditions, espe-
cially in metabolic diseases and cancer. These data also provide
new possibilities of using vitamin A derivates different from RA
(already used as a chemotherapeutical agent in some malignancies,
for review see [82]) for therapeutical strategies.
ACKNOWLEDGEMENTS
We thank Dr. Mike Rogers for correcting the manuscript.
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