A conserved region in the hormone-dependent activation domain AF2 of nuclear receptors plays an important role in
transcriptional activation. Cavailles et al 1995 have characterized a novel nuclear protein, RIP140, that specifically interacts in vitro
with this domain of the estrogen receptor. This interaction was increased by estrogen, but not by anti-estrogens and the
in vitro binding capacity of mutant receptors correlates with their ability to stimulate transcription. RIP140 also
interacts with estrogen receptor in intact cells and modulates its transcriptional activity in the presence of estrogen, but
not the anti-estrogen 4-hydroxytamoxifen.
NCBI Summary:
Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of nuclear receptors. Also known as RIP140, this protein modulates transcriptional activity of the estrogen receptor.
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Cumulus expansion, Ovulation, Follicle rupture
Comment
The Nuclear Receptor Cofactor Receptor-Interacting Protein 140 Is a Positive Regulator of Amphiregulin Expression and Cumulus Cell-Oocyte Complex Expansion in the Mouse Ovary. Nautiyal J et al. The nuclear receptor cofactor receptor-interacting protein 140 (RIP140) is essential for cumulus cell-oocyte complex (COC) expansion, follicular rupture, and oocyte release during ovulation. The expression of many genes necessary for COC expansion is impaired in the absence of RIP140, but the studies herein document that their expression can be restored and COC expansion rescued by treatment with the epidermal growth factor (EGF)-like factor amphiregulin (AREG) both in vitro and in vivo. We demonstrate by several approaches that RIP140 is required for the expression of the EGF-like factors in granulosa cells, but the dependence of genes involved in cumulus expansion, including Ptgs2 Has2, Tnfaip6, and Ptx3, is indirect because they are induced by AREG. Treatment of granulosa cells with forskolin to mimic the effects of LH increases AREG promoter activity in a RIP140-dependent manner that 1) requires an intact cAMP response element in the proximal promoter region of the Areg gene and 2) involves its actions as a coactivator for cAMP response element-binding protein/c-Jun transcription factors. Although human chorionic gonadotropin and AREG coadministration is sufficient to restore ovulation fully in RIP140 heterozygous mice in vivo, both follicular rupture and ovulation remain impaired in the RIP140 null mice. Thus, we conclude that although the level of RIP140 expression in the ovary is a crucial factor required for the transient expression of EGF-like factors necessary for cumulus expansion, it also plays a role in other signaling pathways that induce follicular rupture.
Role of the RIP140 corepressor in ovulation and adipose biology Steel JH, et al .
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.
Multiple signalling defects in the absence of RIP140 impair both cumulus expansion and follicle rupture Tullet JM, et al .
The nuclear receptor corepressor RIP140 is essential in the ovary for ovulation but is not required for follicle growth and luteinization. To identify genes that may be subject to regulation by RIP140 or play a role in ovulation we compared ovarian gene expression profiles in untreated immature wild-type and RIP140 null mice and after treatment with PMSG and hCG. Many genes involved in signaling, extracellular matrix formation, cell-cell attachment and adhesion were aberrantly regulated in the absence of RIP140, varying according to the hormone status of the mice. Notable among these was the reduced expression of a number of genes that encode components of signaling pathways and matrix proteins required for cumulus expansion, a key remodelling process necessary for ovulation. Histological analysis confirmed that cumulus expansion in RIP140 null mice is reduced, oocyte detachment from the mural cell wall is impaired and follicles fail to rupture in response to LH. While the expression of many genes involved in cumulus cell expansion was reduced there was a subset of genes involved in extracellular matrix formation and cell-cell interactions that were upregulated and may interfere with ovarian tissue remodelling. We propose that widespread gene dysregulation in ovarian tissues in the absence of RIP140 leads to the anovulatory phenotype. This helps to define an important role for RIP140 in the regulation of multiple processes leading to ovulation.
Multiple signalling defects in the absence of RIP140 impair both cumulus expansion and follicle rupture Tullet JM, et al .
The nuclear receptor corepressor RIP140 is essential in the ovary for ovulation but is not required for follicle growth and luteinization. To identify genes that may be subject to regulation by RIP140 or play a role in ovulation we compared ovarian gene expression profiles in untreated immature wild-type and RIP140 null mice and after treatment with PMSG and hCG. Many genes involved in signaling, extracellular matrix formation, cell-cell attachment and adhesion were aberrantly regulated in the absence of RIP140, varying according to the hormone status of the mice. Notable among these was the reduced expression of a number of genes that encode components of signaling pathways and matrix proteins required for cumulus expansion, a key remodelling process necessary for ovulation. Histological analysis confirmed that cumulus expansion in RIP140 null mice is reduced, oocyte detachment from the mural cell wall is impaired and follicles fail to rupture in response to LH. While the expression of many genes involved in cumulus cell expansion was reduced there was a subset of genes involved in extracellular matrix formation and cell-cell interactions that were upregulated and may interfere with ovarian tissue remodelling. We propose that widespread gene dysregulation in ovarian tissues in the absence of RIP140 leads to the anovulatory phenotype. This helps to define an important role for RIP140 in the regulation of multiple processes leading to ovulation.
Expression regulated by
LH, Steroids
Comment
Gonadotropin regulation of RIP140 messenger ribonucleic acid expression in the rat ovary. Seo YM et al. Female mice null for receptor-interacting protein 140 (RIP140) are infertile because of the failure of follicle rupture. The present study examined gonadotropin regulation of RIP140 expression in immature rat ovary. Treatment with PMSG increased ovarian RIP140 mRNA and protein levels. In contrast, hCG treatment rapidly inhibited RIP140 mRNA and protein levels within 1-3 h. RIP140 mRNA was detected in theca cells of growing follicles in untreated ovary and in granulosa cells in PMSG-treated ovary. Interestingly, hCG treatment reduced RIP140 mRNA levels in granulosa cells of preovulatory follicles, but not of growing follicles. Neither treatment of immature rats with diethylstilbestrol in vivo nor of immature granulosa cells with FSH in vitro affected RIP140 mRNA levels. Treatment of immature granulosa cells with 17beta-estradiol in vitro, however, stimulated RIP140 mRNA levels. In cultured preovulatory granulosa cells, RIP140 mRNA levels were stimulated at 1 h and then declined to below control levels by 3 h after LH treatment. Treatment with MDL-12,330A, an inhibitor of adenylate cyclase, or chelerythrine chloride, an inhibitor of protein kinase C (PKC), inhibited LH-stimulated RIP140 gene expression. Furthermore, forskolin or TPA treatment for 1 h mimicked the stimulatory action of LH, indicating the involvement of both adenylate cyclase and PKC pathways. These results demonstrate the stimulation by PMSG and inhibition by hCG of RIP140 expression in granulosa cells of preovulatory follicles in the rat ovary.
Ovarian localization
Granulosa, Luteal cells
Comment
G? Leonardsson, et al 2002 reported that
Embryo Transfer Experiments and Ovarian
Transplantation Identify the Ovary as the Only Site in
Which Nuclear Receptor Interacting Protein 1/RIP140 Action Is Crucial for
Female Fertility .
In this study the authors investigated whether the nuclear receptor corepressor nuclear receptor interacting protein 1
(Nrip1)/RIP140, which is essential for ovulation, is also required for postovulatory events, leading to pregnancy and
parturition. Expression analysis indicated that Nrip1 is present in the uterus in stromal and glandular epithelial cells,
primary decidual cells, and subsequently in differentiating decidual cells at the anti-mesometrial side of the implantation
site. It also indicated a temporal regulation of Nrip1 in the corpora lutea at different stages of pregnancy, with increased
levels at midgestation at approximately d 9.5 postcoitum (pc). By performing both embryo and ovarian transfer experiments
it wase demonstrated that, provided the block to ovulation is by-passed, Nrip1-/- mice are capable of establishing and maintaining
pregnancies. However, although the majority of offspring derived from ovarian transplantation survived, approximately 50%
of embryos were resorbed by d 13.5 pc after embryo transfer, and the majority of pups were stillborn or died soon
thereafter. Thus, although Nrip1 is differentially expressed in the reproductive tract, the ovary is the only
site in which its action is essential for fertility, with a crucial role in ovulation and a secondary role in the maintenance of
pregnancy.
Follicle stages
Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:White R, et al 2000 reported that the nuclear receptor co-repressor Nrip1 (RIP140) is essential
for female fertility.
Mice null for this
protein are viable, but female mice are infertile because of complete failure
of mature follicles to release the oocyte at ovulation. In contrast,
luteinization proceeds normally, resulting in a phenotype closely resembling
that of luteinized unruptured follicle syndrome, often associated with
infertility in women. Therefore, whereas the pre-ovulatory surge of
luteinizing hormone induces both ovulation and luteinization, the ability to
suppress the action of nuclear receptors is essential for the coordinated
control of ovarian function with the essential process of oocyte release
dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40).