Identification of RIP140 as a nuclear receptor cofactor with a role in female reproduction (original) (raw)
Related papers
Role of the RIP140 corepressor in ovulation and adipose biology
Journal of Endocrinology, 2005
RIP140 is a ligand-dependent corepressor for most, if not all, nuclear receptors. It is expressed widely in many different tissues, but the phenotype of mice devoid of RIP140 indicates that it plays a crucial role in the ovary and in adipose biology. Ovarian expression of RIP140 is cell-type-specific during follicular development and it is essential for oocyte release during ovulation, but not for luteinization of mature ovarian follicles. In adipose tissue, RIP140 is essential for normal fat accumulation and RIP140-null mice show decreased lipid storage even on a high-fat diet, with upregulation of mitochondrial uncoupling protein (UCP1) in some fat depots. Thus RIP140 plays a crucial role in female fertility and in energy homeostasis, and could be a target for infertility treatment, new contraceptive strategies or prevention of obesity.
The nuclear receptor transcriptional coregulator RIP140
Nuclear Receptor Signaling, 2006
The nuclear receptor superfamily comprises ligand-regulated transcription factors that control various developmental and physiological pathways. These receptors share a common modular structure and regulate gene expression through the recruitment of a large set of coregulatory proteins. These transcription cofactors regulate, either positively or negatively, chromatin structure and transcription initiation. One of the first proteins to be identified as a hormone-recruited cofactor was RIP140. Despite its recruitment by agonist-liganded receptors, RIP140 exhibits a strong transcriptional repressive activity which involves several inhibitory domains and different effectors. Interestingly, the RIP140 gene, located on chromosome 21 in humans, is finely regulated at the transcriptional level by various nuclear receptors. In addition, the protein undergoes several post-translational modifications which control its repressive activity. Finally, experiments performed in mice devoid of the R...
RIP 140 enhances nuclear receptor-dependent transcription in vivo in yeast
Molecular …, 1997
RIP140 has previoulsy been cloned as a factor that interacts with the estrogen receptor (ER) in vitro. We demonstrate in this study that RIP140 is a cofactor for nuclear receptor in yeast. RIP140 enhances the ER transcriptional activity by increasing 1.5-to 4-fold the induction factor of the reporter gene response at saturating hormone concentrations, this effect being magnified at suboptimal doses of estradiol. Moreover, RIP140 decreases the ED 50 of the dose-response curve. These effects are recovered with an N-terminal truncated ER, but impaired by point mutations that abolish AF2-AD activity. We did not observe any modulation of the partial agonist 4-hydroxytamoxifen activity in the presence of RIP140. Thus, RIP140 modulates transcriptional activity of ER through the AF2-AD domain and in a agonist-dependent fashion. RIP140 is also a strong coactivator for the retinoid pathway, as its expression enhances 10-fold the transactivation of a chimeric retinoic acid-␣ receptor at saturant hormone concentration and left shifted 5-fold the ED 50 of the dose-response curve. We have investigated whether RIP140 could be involved in cross-talk between estrogenic and retinoid pathways. (Molecular Endocrinology 11: 193-202, 1997)
RIP-140 interacts with multiple nuclear receptors by means of two distinct sites
Molecular and Cellular Biology, 1996
We have characterized two distinct binding sites, called site 1 and site 2, in the nuclear protein RIP-140 which interact with the ligand binding domain of the estrogen receptor both in solution and when the receptor is bound to DNA. Both sites are capable of independently interacting with other nuclear receptors, including the thyroid hormone and retinoic acid receptors, but they are not identical since the interaction with retinoid X receptor is mediated primarily by site 1. The interaction is enhanced by agonists but not by antagonists, and the in vitro binding activities to a number of mutant receptors correlate with their abilities to stimulate transcription in vivo. When RIP-140 is fused to heterologous DNA binding domains, it is able to stimulate the transcription of reporter genes in both yeast and mammalian cells. Thus, RIP-140 is likely to function as a bridging protein between receptors and the basal transcription machinery and thereby stimulate the transcription of targe...
Negative regulation of hormone signaling by RIP140
Journal of Steroid Biochemistry and Molecular Biology, 2006
Receptor interacting protein (RIP) 140 is a negative transcriptional regulator of nuclear hormone receptors which is required for the maintenance of energy homeostasis and ovulation. Despite its recruitment by agonist-liganded receptors, this protein exhibits a strong repressive activity which was initially attributed to competition with coactivator binding on nuclear receptors. However, RIP140 also exerts active repression implicating the Carboxyl-terminal binding proteins (CtBPs) and histone deacetylases (HDACs). We recently demonstrated that the Carboxyl-terminal region of the molecule contains two additional silencing domains which require post-translational modifications to be fully active. In human breast cancer cells, RIP140 expression is up-regulated at the transcriptional level by various ligands of nuclear receptors. We have recently cloned the human RIP140 gene and defined the mechanism of its regulation by estrogens. In order to better characterize the role of RIP140 in hormone signaling, we have studied its interaction with the androgen receptor and demonstrated its ability to repress transcriptional regulation by androgens. RIP140 also inhibits transactivation by estrogen receptor-related receptors (ERR␣,  and ␥) on natural or artificial reporter genes containing different types of response elements. Surprisingly, RIP140 positively regulates ERR transactivation when the receptors are recruited to target promoters through interaction with the Sp1 transcription factor and this effect could involve titration of histone deacetylases. Altogether, these results underline that transcriptional regulation of hormone signaling by the cofactor RIP140 involves complex mechanisms relying on multiple domains and partners.
Metabolic regulation by the nuclear receptor corepressor RIP140
Trends in Endocrinology & Metabolism, 2006
Whereas the importance of activating gene expression in metabolic pathways to control energy homeostasis is well established, the contribution of transcriptional inhibition is less well defined. In this review we highlight a crucial role of RIP140, a transcriptional corepressor for nuclear receptors, in the regulation of energy expenditure. Mice devoid of the RIP140 gene are lean, exhibit resistance to high-fat-diet-induced obesity, and have increased glucose tolerance and insulin sensitivity. Consistent with these observations, RIP140 suppresses the expression of gene clusters that are involved in lipid and carbohydrate metabolism, including fatty acid oxidation, oxidative phosphorylation and mitochondrial uncoupling. Therefore, the functional interplay between transcriptional activators and the corepressor RIP140 is an essential process in metabolic regulation.
Role of RIP140 in metabolic tissues: Connections to disease
FEBS Letters, 2008
The control of physiological processes requires the regulation and coordination of many different signals and is determined in part by the activation and repression of expression of specific target genes. RIP140 is a ligand dependent coregulator of many nuclear receptors that influence such diverse processes as muscle metabolism, adipocyte and hepatocyte function, and reproduction. Recent evidence has shown that the ability of RIP140 to regulate nuclear receptor function is determined by the relative level of RIP140 expression in comparison with other cofactors, by post-translational modifications and by interactions with additional transcription factors. As a result it is becoming apparent that RIP140, via its interplay with other coregulators, plays a fundamental role in determining both the normal and pathogenic physiological state.
The nuclear receptor co-repressor RIP140 controls the expression of metabolic gene networks
Biochemical Society Transactions, 2006
NRs (nuclear receptors) regulate the expression of specific gene networks in target cells by recruiting cofactor complexes involved in chromatin remodelling and in the assembly of transcription complexes. The importance of activating gene expression, in metabolic tissues, is well established, but the contribution of transcriptional inhibition is less well defined. In this review, we highlight a crucial role for RIP140 (receptor-interacting protein 140), a transcriptional co-repressor for NR, in the regulation of metabolic gene expression. Many genes involved in lipid and carbohydrate metabolism are repressed by RIP140 in adipose and muscle. The repressive function of RIP140 results from its ability to bridge NRs to repressive enzyme complexes that modify DNA and histones. In the absence of RIP140, expression from many metabolic genes is increased so that mice exhibit a lean phenotype and resistance to high-fat-diet-induced obesity and display increased glucose tolerance and insulin ...
Molecular and Cellular Biology, 2001
CtBP (carboxyl-terminal binding protein) participates in regulating cellular development and differentiation by associating with a diverse array of transcriptional repressors. Most of these interactions occur through a consensus CtBP-binding motif, PXDLS, in the repressor proteins. We previously showed that the CtBP-binding motif in E1A is flanked by a Lys residue and suggested that acetylation of this residue by the p300/CBPassociated factor P/CAF disrupts the CtBP interaction. In this study, we show that the interaction between CtBP and the nuclear hormone receptor corepressor RIP140 is regulated similarly, in this case by p300/CBP itself. CtBP was shown to interact with RIP140 in vitro and in vivo through a sequence, PIDLSCK, in the amino-terminal third of the RIP140 protein. Acetylation of the Lys residue in this motif, demonstrated in vivo by using an acetylated RIP140-specific antibody, dramatically reduced CtBP binding. Mutation of the Lys residue to Gln resulted in a decrease in CtBP binding in vivo and a loss of transcriptional repression. We suggest that p300/CBP-mediated acetylation disrupts the RIP140-CtBP complex and derepresses nuclear hormone receptor-regulated genes. Disruption of repressor-CtBP interactions by acetylation may be a general mode of gene activation.