Advances in Bioscience and Biotechnology, 2013, 4, 45-54 ABB Published Online October 2013 (
Dialogue between estrogen receptor and E2F signaling
pathways: The transcriptional coregulator RIP140 at the
Marion Lapierre1,2,3,4, Aurélie Docquier1,2,3,4, Audrey Castet-Nicolas1,2,3,4, Stéphan Jalaguier1,2,3,4,
Catherine Teyssier1,2,3,4, Patrick Augereau1,2,3,4, Vincent Cavaillès1,2,3,4
1IRCM—Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
2INSERM, U896, Montpellier, France
3Université Montpellier1, Montpellier, France
4Institut Régional du Cancer Montpellier, Montpellier, France
Received 25 July 2013; revised 25 August 2013; accepted 19 September 2013
Copyright © 2013 Marion Lapierre et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Estrogen receptors and E2F transcription factors are
the key players of two nuclear signaling pathways
which exert a major role in oncogenesis, particularly
in the mammary gland. Different levels of dialogue
between these two pathways have been deciphered
and deregulation of the E2F pathway has been shown
to impact the response of breast cancer cells to endo-
crine therapies. The present review focuses on the
transcriptional coregulator RIP140/NRIP1 which is
involved in several regulatory feed-back loops and
inhibitory cross-talks between different nuclear sig-
naling pathways. RIP140 regulates the transactiva-
tion potential of estrogen receptors and E2Fs and is
also a direct transcriptional target of these transcrip-
tion factors. Published data highlight the complex re-
gulation of RIP140 expression at the transcriptional
level and its potential role in transcription cross-talks.
Indeed, a subtle regulation of RIP140 expression lev-
els has important consequences on other transcrip-
tion networks targeted by this coregulator. Another
level of regulation implies titration mechanisms by
which activation of a pathway leads to sequestration
of the RIP140 protein and thus impinges other gene
regulatory circuitries. Altogether, RIP140 occupies a
place of choice in the dialogue between nuclear re-
ceptors and E2Fs, which could be highly relevant in
various human pathologies such as cancer or metabo-
lic diseases.
Keywords: RIP140; E2F Transcription Factors;
Estrogen Receptors; Gene Expression; Cell Proliferation;
Breast Cancer; Endocrine Therapies
1.1. Estrogen Signaling in Breast Cancer Cells
Estrogens are steroid hormones that regulate growth and
differentiation of a large number of target tissues such as
the mammary gland, the reproductive tract and skeletal
and cardiovascular systems [1]. Most of these events are
mediated through two distinct intracellular receptors,
ERα and ERβ, which belong to the superfamily of nu-
clear receptors. ERs bind as homo- or heterodimers to
specific DNA response elements (EREs) located within
the regulatory regions of target genes. Indirect recruit-
ment on target promoters also occurs through protein-
protein interaction with other transcription factors, such
as Sp1 or AP-1. The ligand-dependent transcriptional ac-
tivity of ERs is mediated by two distinct activation do-
mains, a constitutive activation function-1 (AF-1) located
within the N-terminus of the molecule and a hormone-
dependent transactivation domain AF-2, associated with
the ligand-binding domain. Depending on cell and pro-
moter contexts, these two domains function independent-
ly or synergistically. Ligand binding induces a conforma-
tional change that facilitates the recruitment of a large set
of coactivator proteins [2]. These transcription mediators
act either by stabilizing the formation of a transcription
preinitiation complex or by facilitating chromatin disrup-
tion through various enzymatic activities that target hi-
stone tails. On the other hand, ERα has been shown to in-
*Role of RIP140 in estrogen and E2F pathways.
M. Lapierre et al. / Advances in Bioscience and Biotechnology 4 (2013) 45-54
teract specifically with corepressors such as the MTA1/
NuRD chromatin-remodeling complex or NCOR1 in the
presence of partial antiestrogens such as 4-hydroxyta-
moxifen. Estrogens stimulate cell proliferation in normal
developing breast tissues and in a large proportion of
ERα-positive breast cancers. Endocrine therapies using
selective estrogen receptor modulators or aromatase inhi-
bitors have proven their efficacy in the prevention or
treatment of breast cancer [3]. The role of estrogens in
breast cancer cells appears more complex since in addi-
tion to its classical genomic actions, ERα also exerts rapid
non-genomic effects, which involve interaction with dif-
ferent signal transduction proteins including the tyrosine
kinase Src and the phosphatidylinositol 3-kinase (PI3K)
[4]. In addition, the estrogen signaling pathway is finely
regulated by multiple post-translational modifications
which regulate its function and play important roles in
physiopathology [5].
1.2. E2F Transcription Factors
E2Fs and their heterodimer partners, DPs, are central re-
gulators of cell cycle progression and directly regulate
the expression of a broad spectrum of genes involved in
cell cycle regulation, DNA replication and repair, apop-
tosis, differentiation or development [6]. E2F1, discov-
ered as a protein promoting the transition to S phase, was
the founding member of the E2F family which comprises
eight members in mammals. Among this family, some
were initially presented as “activator E2Fs’’ (E2F1, 2 and
3) while the other members were mostly known as tran-
scription repressors. E2F transcriptional activity was
shown to be regulated by a large number of transcription
coactivators or corepressors including the so-called poc-
ket proteins which form the retinoblastoma tumor sup-
pressor family (RB together with the related proteins
p107 and p130) [7]. RB attenuates activator E2F action
by recruiting transcriptional corepressors such as histone
deacetylases (HDACs) to E2F-regulated promoters, thus
mediating transcriptional repression of E2F-regulated
genes. RB is a critical component of the cell cycle con-
trol machinery and as a consequence, its loss or inactiva-
tion is a major mechanism by which cancer cells attain a
growth advantage during tumorigenesis [8].
1.3. Cr oss-Talks between ER and E2F Signalings
1.3.1. Regula tion of ER Signal i ng by E2F s and Pocket
A first dialogue between the two pathways deals with the
regulation of ER and nuclear receptor coregulator ex-
pression by the E2F pathway. The ERα promoter con-
tains two E2F binding sites in the proximal promoter
region and it has been demonstrated that multimolecular
complexes containing E2F4/5 are recruited on the ERα
promoter in cycling MCF-7 and MDA-MB-231 breast
cancer cell lines [9]. This suggests that the E2F pathway
might be involved in the transcriptional repression of the
ERα gene which occurs in up to one-third of breast can-
cers. Interestingly, a study on human breast cancer biop-
sies confirmed the overexpression of E2F5 in ERα-ne-
gative breast cancers and its association with a worse
outcome [10]. Steroid receptor coactivator 3 (SRC3/
NCOA3), a major transcriptional coactivator for estrogen
receptors which is overexpressed in breast cancers, is
also a transcriptional target of E2F transcription factors.
In MCF-7 breast cancer cells, SRC3 expression is under
the control of E2F1 (ectopic expression increases SRC3
levels whereas knockdown of E2F1 reduces SRC3 ex-
pression) [11]. The regulation operates at the transcrip-
tional level and involves Sp1 response element in the
proximal promoter region. At the transactivation level,
RB has been shown to potentiate the enhancing effect of
SRC2/NCOA2 on both ERα and ERβ activity [12] and
an interaction between ERβ and p130 has been reported
although the relevance of this interaction has not been
investigated [13]. RB can also interact indirectly with
ERα through the RIZ protein [14]. Finally, other mem-
bers of the E2F pathway such as Cdc25B [15] or cyclin-
cdk complexes [16] have also been described as modu-
lators of ER activity.
1.3.2. Regulation of the E2F Pathway by Estrogens
A main level of cross-talk between ER and E2F signaling
pathways resides in the regulation of E2F1 expression by
estrogens. This regulation has been observed at the
mRNA level in several breast cancer cell types such as
MCF-7, ZR75-1 or T47D cells [17]. Recently, ChIP ex-
periments confirmed the presence of ERα on the E2F1
promoter [18]. The regulation was also detected at the
E2F1 protein level which was significantly increased
upon E2 treatment [19]. The regulation of E2F1 levels
appears critical for the mitogenic effect of estrogens
since silencing of E2F1 expression in MCF-7 breast can-
cer cells resulted in a loss of estrogen regulation of cell
proliferation [19]. Whereas E2F1 mRNA levels are strong-
ly increased by estrogens in MCF-7 cells, the expression
of E2F2 and E2F6 mRNA is only weakly increased and
that of E2F3-5 not affected [19]. However, another study
reported the regulation of E2F1, E2F2, E2F7 and E2F8
mRNA by E2 in MCF-7 cells, all being sensitive to pro-
tein synthesis inhibition [20]. It should be noted that the
induction of E2F1 by estrogens is modulated by various
factors such as SCFskp2 [18], the IκB kinase (IKKα) [21]
or the transcription factor HES-1 [22]. Estrogens treat-
ment also impacts the E2F signaling pathway at other le-
vels by increasing the formation of active Cyclin D1-
Cdk4 complexes in MCF-7 cells and increasing the
phosphorylation of pRB or by regulating the expression
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M. Lapierre et al. / Advances in Bioscience and Biotechnology 4 (2013) 45-54 47
of other members of the pathway such as the Cdk-activa-
ting phosphatase Cdc25A [23-25]. Another point deals
with the fact that nuclear receptor coregulators such as
CBP [26], PCAF [27], ASC-2/ NCOA6 [28] or AIB1/
NCOA3 [29] interact with E2F and modulate its tran-
scriptional activity. The specific role of the nuclear re-
ceptor corepressor RIP140 in the regulation of E2F ac-
tivity is discussed below.
1.3.3. E2F Signaling and Regulation of Cell
Pro liferati on by Estrogens and Antiestrogens
Approximately 70% of breast cancers are ER-positive tu-
mors and patients bearing such tumors are treated with
endocrine therapies which comprise selective ER modu-
lators such as Tamoxifen, aromatase inhibitors which tar-
get estrogen synthesis such as Letrozole or pure ER an-
tagonists such as Fulvestrant [30]. Although hormonal
interventions have proven to be very effective in breast
cancer treatment, many patients develop drug resistance
which represents a major clinical problem [31]. The me-
chanisms by which tumors escape from endocrine thera-
pies are not fully understood and several signaling path-
ways have been involved in the bypass of these treat-
ments [30]. One mechanism by which cells overcome the
inhibition of ER signaling is linked to the activation of
the Cyclin/Cdk/RB/E2F. In MCF-7 breast cancer cells,
antiestrogens reduce the level of Cdk2 activity and de-
crease the level of hyperphosphorylated RB [32,33].
Moreover, the group of E Knudsen demonstrated that si-
lencing of RB expression or ectopic expression of E2F3
compromised the short-term cell-cycle inhibition by an-
tiestrogen resulting in continued cell and tumor prolif-
eration in the presence of Tamoxifen [34]. By reanalyz-
ing microarray datasets, the deregulation of RB/E2F tar-
get gene expression was shown to be strongly associated
with recurrence in patients treated with Tamoxifen. More
recently, the perturbation of the transcriptional response
to RB was confirmed in antiestrogen-resistant MCF7-de-
rived cell models [35] and an estrogen-independent role
for ERα demonstrated in driving an E2F transcriptional
program [36]. This study also reported that an E2F acti-
vation gene signature correlates with a decrease in pa-
tient response to aromatase inhibitors. Altogether, these
studies support the idea that hyperactivation of the E2F
signaling pathway is a key determinant of the response to
hormonal therapies [37].
2.1. Introduction
Almost 20 years ago, one of the main goals in the field of
nuclear receptor (NR) biology was to identify interacting
partners acting as transcriptional coregulators. RIP140
(Receptor Interacting Protein of 140 kDa) also known as
Nuclear receptor-interacting protein 1 (NRIP1), was one
of the first NR coregulator to be isolated from human
cancer cells by far-western blotting using the ligand bin-
ding domain of the mouse ERα as a radiolabeled probe
[38,39]. Although RIP140 has been first described as a
repressor of gene expression, it can also activate transcri-
ption depending on the target transcription factors and
promoters considered (see below). The human RIP140
protein is a polypeptide of 1158 amino acids which is
well conserved across species. It contains two putative
nuclear localization signals and several other domains
important for its biological activity as a transcription fac-
tor. Four repressive domains (RD) have been identified
in the RIP140 molecule [40,41]. The RD1 acts mainly by
recruiting class I and II histone deacetylases (HDACs)
whereas the RD2 interacts with carboxyl-terminal-bind-
ing proteins (CtBP1 and CtBP2) through two conserved
motifs (sequences PIDLS and PINLS) [42,43]. No down-
stream effectors have yet been identified for RD3 and
RD4 which are located in the carboxyl-terminal region of
the molecule (amino acid residues 753 - 804 and 1118 -
1158, respectively). Interestingly, two lysine residues lo-
cated in these domains are conjugated to SUMO proteins
and play an important role in controlling the repressive
activity of RIP140 [44]. Extensive biochemical studies
performed in the laboratory of L Wei have revealed a
complex network of post-translational modifications (e.g.
phosphorylation, acetylation or methylation) which target
the RIP140 protein and affect various parameters such as
its subcellular localization, interaction with partners and
transcriptional regulation. Mainly as a consequence of
some of these post-translational modifications, RIP140
could be delocalized in the cytoplasm where it exerts dif-
ferent functions. A first example deals with the regulation
of glucose uptake through the control of glucose trans-
porter type 4 (GLUT4) trafficking which involves inter-
action with the 160-KDa Akt substrate, AS160 [45]. An-
other effect of cytoplasmic RIP140 has been demonstrat-
ed in lipid metabolism of adipocytes with a positive re-
gulation of lipolysis through its direct interaction of
RIP140 with perilipin [46]. Besides its interaction with
various members of the NR superfamily, RIP140 has also
been evidenced as a regulator of other transcription fac-
tors like the aryl hydrocarbon receptor (AhR) [47]. More
recently, it has been shown that, in murine macrophages,
RIP140 positively controls the expression of proinflam-
matory genes such as IL1β, IL6 or TNFα [48]. The ability
of RIP140 to function as a transcriptional activator of
cytokine gene transcription relies on direct protein-pro-
tein interactions with the NFκB subunit RelA and histone
acetylase cAMP-responsive element binding protein
(CREB)-binding protein (CBP). Using genetically ma-
nipulated mice (mainly constitutive gene knockout mice),
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M. Lapierre et al. / Advances in Bioscience and Biotechnology 4 (2013) 45-54
several laboratories have deciphered the physiological
roles of RIP140, highlighting a wide spectrum of major
phenotypes dealing for instance with metabolism, repro-
duction, heart and mammary gland physiology or behav-
ior [49,50].
2.2. RIP140 as a Regulator of Estrogen Signaling
2.2.1. Interaction of RIP140 with ERα
RIP140 was originally identified as a repressor of the
estrogen receptor ERα in human breast cancer cells [39].
As transcription coactivators, RIP140 is recruited to ERα
in the presence of agonist by means of short helical mo-
tifs which exhibit the LXXLL consensus amino acid se-
quence. These motifs facilitate protein-protein interac-
tions and docking on NR ligand-binding domains in their
apo conformation. The RIP140 protein contains nine
LxxLL motifs thus offering a great diversity in term of
NR interaction [51]. Depending on the promoter context
and post-translational modifications, this conformational
adaptation allows RIP140 to function as a scaffold for
the assembly of chromatin remodeling complexes. Sev-
eral studies have demonstrated the ligand-dependent re-
cruitment of RIP140 on target genes in intact cells using
the chromatin immunoprecipitation technique. This was
for instance described on the RARα promoter in the pre-
sence of E2 [52]. A recent paper reported a ChIP-Seq
analysis of RIP140 target genes in MCF-7 cells treated
by 17β-estradiol [53]. Surprisingly, this whole-genome
binding sites analysis revealed only 2000 binding sites
for RIP140 representing less than 5% of the genes tar-
geted by ERα in the same conditions.
2.2.2. Effect of RIP140 on ERα and ERβ
One of the hypotheses to explain the inhibitory effect of
ERβ on E2 regulation of gene expression and cell prolif-
eration implies a differential recruitment of transcriptio-
nal coregulators by the two ER subtypes. Previous stud-
ies have reported ERβ [54,55] or ERα [56,57] specific
interaction with different coregulators. A recent analysis
of the nuclear interactomes of the two ER subtypes re-
vealed only a small set of common proteins [58]. Inter-
estingly, using various approaches (GST pull down, ani-
sotropy measurements, FCCS and ChIP assays), we have
recently demonstrated that RIP140 was preferentially in-
teracting with ERβ as compared with ERα [59]. More-
over, our results obtained after siRNA-mediated knock-
down of RIP140 expression in BG1 ovarian cancer cells
demonstrated the key role of RIP140 in the repressive ef-
fect exerted by activated ERβ on the regulation of ERE-
controlled transcription by estrogens. This preferential
interaction of RIP140 with ERβ was supported by global
ChIP-Seq analysis showing that, in MCF-7 breast cancer
cells, the number of RIP140-binding sites was increased
by about 4-fold upon ERβ expression [53].
2.2.3. Ternary Complex Involving ERs and RIP140
In addition to the ERE-mediated regulation of gene ex-
pression, ERs are involved in protein-protein interaction
with other transcription factors such as Sp1 or AP1 [60,
61]. In some cases, it has been reported that such com-
plex are also regulated by RIP140. For instance, AP1-
mediated transcription is increased by ERα through a
direct interaction with c-Jun and the recruitment of the
coactivator GRIP1/NCOA2. This estradiol-induced AP-
1-dependent transcription is inhibited by RIP140 in a
dose-dependent manner [62]. In HepG2 cells, the inhibi-
tion of the PROS1 gene transcription by estrogen involv-
es the interaction of ER with Sp proteins and the re-
cruitment of RIP140 and a NCoR-SMRT-HDAC3 com-
plex on the proximal region of the PROS1 promoter, as
demonstrated by chromatin immunoprecipitation assays
[63]. Another crosstalk involves the aryl hydrocarbon re-
ceptor (AhR) which interacts with ERα and inhibits E2
target genes when activated by ligands such as polycyclic
aromatic or halogenated hydrocarbons. Different mecha-
nisms have been reported involving proteasomal degra-
dation of ERα [64] or squelching of common coactiva-
tors [65]. More recently, a new mechanism by which
AhR regulates ERα action in breast cancer cells has been
proposed. It involves the formation of a ternary complex
with RIP140 on ERα-binding sites as demonstrated by
ChIP-reChIP studies on the LRRC54 or HSPB8 gene pro-
moters [66].
2.3. Effects of RIP140 on the E2F Pathway
2.3.1. Interaction of RIP140 with E2Fs
By means of various approaches, the interaction between
RIP140 and E2F1 was clearly demonstrated [67]. Using
in vitro GST pull-down assays, the respective binding
sites on the two proteins were delineated. Two regions of
the RIP140 molecule spanning from amino acids 119 to
199 and 916 to 1158 are involved in the interaction with
the N-terminus of E2F1. Co-immunoprecipitation expe-
riments and ChIP assays confirmed that the interaction
between RIP140 and E2F1 occurs in intact cells.
2.3.2. RI P140 Inh ibits E2F T ar get Gene Exp r e ss ion
In transiently transfected MCF-7 breast cancer cells,
RIP140 ectopic expression resulted in a significant dose-
dependent inhibition of E2F1 activity measured on dif-
ferent E2F reporter promoters such as the CCNE or
CDKN2A promoters. This repressive activity of RIP140
was also observed in other human cancer cell lines and
on the two other activator E2Fs, i.e. E2F2 and E2F3.
Moreover, the expression of several E2F target genes
(CCNE, CCNB2, CDC2 and CDC6) was strongly de-
creased in MCF-7 breast cancer cells overexpressing a
chimaeric GFP-RIP140 protein. However, the negative
regulation was not observed for all E2F-target genes
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M. Lapierre et al. / Advances in Bioscience and Biotechnology 4 (2013) 45-54 49
since for instance, the DHFR mRNA levels were not
significantly affected. In agreement with the inhibition of
E2F activity, RIP140 reduced the proportion of cells in S
phase after ectopic expression in various human cell
2.3.3. Inverse Correlation between RIP140 and E2F
Target Gene Expression
To emphasize the biological significance of E2F inhibi-
tion by RIP140, the expression of RIP140 and E2F1-tar-
get genes were analyzed on a tumor microarray data set
of 170 breast cancer samples [68]. A clustering analysis
clearly showed that, in this cohort of human breast can-
cers, RIP140-deficiency is inversely correlated with the
expression of several E2F1-target genes (CCNE1, MYBL2,
BIRC5, E2F1, CCNB2 and CDC6). Moreover, variations
of RIP140 expression discriminate between molecular
subtypes, low RIP140 mRNA expression being associat-
ed with basal-like tumors.
3.1. Structure and Regulation of the RIP140
The human RIP140 gene is located in a gene-poor region
of chromosome 21 q11.2 [69]. Interestingly, the RIP140
coding sequence is comprised in a single large exon with
several short non-coding exons which undergo alterna-
tive splicing placing the promoter about 100 kb upstream
of the ATG [70]. RIP140 is a widely expressed gene and
in the mouse, the mRNA is detected in all the tissues
with a strong expression in the testis and in the brain [71].
The RIP140 mRNA is present in a large number of can-
cer cell lines where it appears regulated by various nu-
clear receptors [72].
3.2. RIP140 as an Estrogen Induced Gene
We initially reported that RIP140 gene expression was
regulated by 17β-estradiol (E2) in MCF-7 human breast
cancer cells [38]. Several studies using global gene ex-
pression profiling also identified RIP140 as an estrogen-
induced gene in breast cancer MCF-7 cells [19]. More
recently, using the Rank product method, a meta-analysis
of several expression studies provided a list of genes dif-
ferentially expressed upon E2 stimulation [73]. By analy-
zing 9 time-series data sets, the authors identified be-
tween 1000 and 2000 target genes mostly related to cell
signaling and proliferation which exhibit an early regula-
tion by estrogens (i.e. 3-4 hrs post E2 treatment). The
RIP140 gene was well ranked in this list of early up-re-
gulated genes. The regulation of RIP140 expression by
estrogens is independent of protein synthesis [74], direct
(i.e. it does not require synthesis of an intermediary pro-
tein as judged by the absence of effect of cycloheximide)
and operates at the transcriptional level [70]. A consensus
ERE (which binds the ERα in gel shift and ChIP experi-
ments) has been mapped in the 5’ proximal region of the
gene [20,70,75] and it has been proposed that FoxA1
sites might function as an enhancer facilitating the re-
cruitment of ERα on the RI P140 promoter [76]. In MCF-
7 cells, the regulation was preferentially mediated by
ERα as indicated by the use of the specific agonist ligand
4,4’,4”-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol
(PPT). These results were confirmed using HeLa cells
stably transfected with either ERα or ERβ expression
vector [77] or MDA-MB 231 breast cancer cells infected
with recombinant adenovirus expressing either variant of
the ER. In MCF-7 cells, we showed that ER antagonist
ligands such as 4-hydroxy Tamoxifen, Raloxifene or the
pure antiestrogen ICI 182,780 did not increase the stea-
dy-state levels of RIP140 mRNA [70]. The regulation by
estrogens was not restricted to mammary cancer cells
since similar increase of RIP140 mRNA levels by estra-
diol was observed in human ovarian cancer cells [59]. In
addition, transcriptional profilings of ER-regulated genes
using stably transfected U2OS cells expressing either
ERα or ERβ have also identified RIP140 as an E2-re-
gulated gene although the relative induction by the two
isoforms of ER varied according to the study [78,79].
3.3. E2Fs Control RIP140 Transcription
We recently published the identification and characteri-
zation of E2F binding sites in the proximal promoter re-
gion of the RIP140 gene [80]. Using gel shift experi-
ments, we showed that E2F1 strongly interacts with oli-
gonucleotides encompassing the putative binding sites.
ChIP experiments demonstrate that the interaction of
E2F1/DP1 with the proximal promoter region occurred
in intact cells. Moreover, transient transfection experi-
ments demonstrate a transcriptional regulation of the hu-
man and mouse RIP140 promoters by E2F1, E2F2 and
E2F3 and promoter mutagenesis (deletion and point mu-
tations) suggested a complex regulation of the RIP140
promoter by E2F1, involving a combination of direct and
indirect recruitment through Sp1 similar to the regulation
of SRC3 by E2F1 [11]. Interestingly, a significant in-
crease in the levels of endogenous RIP140 mRNA was
observed upon ectopic overexpression of E2F1 and DP1,
thus confirming that RIP140 is a transcriptional target of
E2F1 and could explain the variation in RIP140 expres-
sion observed after cell synchronization.
3.4. Nuclear Cross-Talks Involving RIP140
Auto-and cross-regulation between members of the nu-
clear receptor superfamily appear important for the coor-
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M. Lapierre et al. / Advances in Bioscience and Biotechnology 4 (2013) 45-54
dination of hormone action in a temporal and tissue-spe-
cific manner and for the regulation of hormonal signals
through positive or negative feedbacks [81]. Several in-
direct transcriptional cross-talks involving the regulation
of RIP140 gene expression have been reported. Treat-
ment of MCF-7 cells with 2,3,7,8-tetrachlorodi-benzo-p-
dioxin (TCDD), an agonist of the arylhydrocarbon recep-
tor (AhR) induced a two-fold increase in RIP140 mRNA
steady state level [70]. This TCDD-mediated increase in
RIP140 expression could lead to a transrepression of ER
activity and thus participate in the antiestrogenic effect of
AhR [82,83]. RIP140 mRNA expression was also shown
to be induced by all-trans retinoic acid in human embry-
onic carcinoma cells and in MCF-7 cells [84], suggesting
that RIP140 might mediate some of the anti-estrogenic
effects of retinoic acid [85]. Indeed, RIP140 knock-down
using siRNA reverse the antiestrogenic effect of retinoic
acid on an ERE-mediated transcriptional response. RIP140
appears to be a limiting factor in the estrogen signaling
pathway since silencing its expression leads to an en-
hancement of the mitogenic effect of estrogens [85]. As a
consequence, the nuclear receptors which positively re-
gulate RIP140 expression (i.e. vitamin D [86], progestin
[87], androgens [88] and ERRs [89]) have all the poten-
tial to inhibit estrogen-induced proliferation. It should be
mentioned that this straightforward interference should
be counterbalanced by the competition of the different
nuclear receptors for a limiting pool of RIP140 protein.
Interestingly, such interference should also exist with the
other transcription factors targeted by RIP140 (E2F,
NFkB…) and further work is necessary to decipher these
different levels of cross-talk.
The interactions between transcription factors and their
target genes play a key role in the regulation of cellular
processes. These molecular circuitries which control the
expression levels of genes are dialoguing with each other
and deregulation of these cross-talks is responsible for a
variety of pathological events such as cancer. The tran-
scriptional coregulator RIP140 is engaged not only in
regulatory feed-back loops but also in repressive cross-
talks occurring between different nuclear signaling path-
ways. RIP140 regulates the transactivation potential of
estrogen receptors and E2Fs and is a direct transcrip-
tional target of these transcription factors. Due to rate-
limiting cellular levels, a subtle regulation of RIP140 ex-
pression (through transcriptional regulation or protein ti-
tration) may have important consequences on the other
transcription networks targeted by this coregulator. This
could be relevant in the case of molecular circuitries in-
volving estrogen receptors and E2F transcription factors
such as resistance to endocrine therapies. Another cell
parameter which could be impacted by such cross-talks
is cell metabolism. RIP140 is a main regulator of cellular
metabolic circuitries and some of these regulations may
involve cross-talks between E2Fs and nuclear receptors.
The present review mainly focuses on dialogue within
the nucleus. However, RIP140 and ERα are also cyto-
plasmic proteins and further work will be necessary to
determine whether RIP140 participates in the regulation
of non-genomic action of estrogens and the nature of
cross-talks in this cellular compartment. Moreover, addi-
tional studies are required to fully decipher the role of
the multiple post-translational modifications of the diffe-
rent partners in cross-talk settings. Finally, RIP140 may
be involved in the regulation of other signaling pathways
which are also interconnected with estrogen receptor path-
ways such as the Wnt or p53 signaling which have been
shown to be important for the resistance to antiestrogens
[90,91]. Further genome wide profiling of RIP140 bind-
ing sites in breast cancer cells is obviously needed to
address these issues.
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