Disease relevance of NRIP1

• By contrast, multilocus analysis predicted epistatic interactions between ESR1, ESR2 and NRIP1 loci and its involvement in postmenopausal osteoporosis (P=0.003) [1].
• In this study, we investigated the mechanisms by which RIP140 expression is controlled by estrogens in breast cancer cells [2].
• METHODS: We have sequenced the complete coding region of NRIP1 gene in 20 unrelated patients affected by endometriosis [3].
• Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions [4].
• The ovarian phenotype observed in mice devoid of rip140 closely resembles the luteinized unruptured follicle (LUF) syndrome that is observed in a high proportion of women affected of endometriosis or idiopathic infertility [3].

High impact information on NRIP1

• A constitutive negative (Arg/Ala) mutant of RIP140 was resistant to the effect of PRMT1, and a constitutive positive (Arg/Phe) mutation mimicked the effect of arginine methylation [5].
• Suppression of receptor interacting protein 140 repressive activity by protein arginine methylation [5].
• This study uncovered a novel means to inactivate, or suppress, RIP140, and demonstrated protein arginine methylation as a critical type of modification for corepressor [5].
• Receptor interacting protein 140 (RIP140), a ligand-dependent corepressor for nuclear receptors, can be modified by arginine methylation [5].
• Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor [6].

Chemical compound and disease context of NRIP1

• Overexpression of RIP140 dose dependently inhibits estrogen-dependent reporter activity in human breast cancer cells [7].
• Through the use of microarray analysis it was discovered that the nuclear receptor coregulator, receptor interacting protein 140 (RIP140), was induced early during all-trans retinoic acid (RA)-induced differentiation of human embryonal carcinoma cells [8].

Biological context of NRIP1

• We proposed a non-additive non-multiplicative oligogenic model including ESR2 AG genotype modulated by NRIP1 A+ or ESR1 TT genotypes involved in osteoporosis [1].
• Although we mapped a perfect consensus estrogen response element able to bind ERalpha in gel shift and in chromatin immunoprecipitation experiments, the effect of E2 on RIP140 gene transcription was very modest [2].
• Altogether, our data indicate that the RIP140 gene exhibits a complex structure with several noncoding exons and supports transcriptional cross-talk and feedback involving the ERalpha and AhR nuclear receptors [2].
• Receptor interacting protein 140 (RIP140) is a negative transcriptional regulator of nuclear hormone receptors that is required for the maintenance of energy homeostasis and ovulation [2].
• This might result at least in part from the presence of an overlapping aryl hydrocarbon receptor (AhR) binding site, which interfered with the E2 response on both the transiently transfected reporter construct and the accumulation of the endogenous RIP140 mRNA [2].

Anatomical context of NRIP1

• Specifically, mice null for nrip1 gene are viable, but females are infertile because of complete failure of mature follicles to release oocytes at ovulation stage [3].
• Transient cotransfection in COS-7 cells, a standard approach to demonstrate coactivation, was used to study the coactivation properties of NuRIP183, a new nuclear receptor interacting protein of 183 kDa, isolated by a yeast two-hybrid screening [9].
• We have shown that expression of steroid receptor coactivator-1 alpha (SRC-1alpha) and receptor interacting protein-140 (RIP-140) have no effect on the capacity of the ERalpha to modulate NFkappaB reporter gene activity in HeLa cells [10].

Associations of NRIP1 with chemical compounds

• Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin signalling [2].
• In contrast, a strong interaction of RIP140 with the PPARalpha and LXRalpha heterodimerization partner retinoid-X-receptor alpha (RXRalpha) required the presence of its cognate ligand, 9-cis retinoic acid [11].
• This interaction appeared physiologically relevant because chromatin immunoprecipitation assays revealed that, under R1881 treatment, RIP140 could be recruited to the prostate-specific antigen encoding gene in LNCaP cells [12].
• Finally, we provided evidence for a stimulation of RIP140 mRNA expression in LNCaP cells under androgen treatment, further emphasizing the role of RIP140 in androgen signaling [12].
• In vitro glutathione S-transferase pull-down assays provided evidence that the carboxy-terminal domain of AR could interact with different regions of RIP140 [12].

Physical interactions of NRIP1

• Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect [13].
• Furthermore, we show that full RIP140 corepressor activity is contributed both by C-terminal receptor-binding LXXLL motifs and interaction with the CtBP corepressor [14].
• The nuclear-receptor interacting protein (RIP) 140 binds to the human glucocorticoid receptor and modulates hormone-dependent transactivation [15].
• RIP140 interacts with retinoic acid receptor (RAR) and retinoid X receptor (RXR) with or without ligands [16].
• Furthermore, constitutive phosphorylation at both Thr202 and Thr207 residues renders RIP140 fully repressive and strongly interacting with HDAC [17].

Regulatory relationships of NRIP1

• We report that overexpression of RIP140 inhibits estradiol-induced AP-1-dependent transcription in a dose-dependent manner [13].
• Overexpression of RIP140 strongly repressed AR-dependent transactivation by preferentially targeting the ligand binding domain-dependent activity [12].
• Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes [18].
• We first show that RIP140 inhibits transactivation by ERRalpha, beta, and gamma on natural or artificial reporter genes containing different types of response elements [18].
• Conjugation of SUMO-1 also influenced the subnuclear distribution pattern of RIP140 [19].

Other interactions of NRIP1

• These overall results suggest that the ratio between RIP140 and GRIP1 could determine, as proposed for hormone response element-mediated responses, the efficacy of estradiol in stimulating transcription of genes under AP-1 control [13].
• We first analyzed by real time reverse transcription-polymerase chain reaction the regulation of RIP140 mRNA accumulation by estrogen receptor (ER) ligands in MCF-7 cells [2].
• Transfection analysis in mammalian cells demonstrated that RIP140 antagonized PPARalpha/RXRalpha- and LXRalpha/RXRalpha-mediated signaling [11].
• Receptor interacting protein 140 (RIP140), a previously identified putative ligand-dependent coactivator of nuclear hormone receptors, was isolated by yeast two-hybrid cloning as a factor that interacts with peroxisome proliferator-activated receptor alpha (PPARalpha) [11].
• We then showed that the carboxy-terminal end of RIP140 could reverse transcriptional intermediary factor 2-dependent overactivation of AR [12].

Analytical, diagnostic and therapeutic context of NRIP1

• Moreover, we found that Arg448Gly, a common polymorphism located within NRIP1 gene, is associated with endometriosis in a case-control study (59 cases and 141 controls, Pallele positivity test = 0.027) [3].
• Using different approaches (titration of endogenous CtBPs, mutagenesis and transfection in CtBP knock-out cells), we find that recruitment of CtBPs only partially explains the negative regulation exerted by RIP140 [20].
• The role of phosphorylation of RIP140 in regulating its biological activity and the underlying mechanism are examined using a site-directed mutagenesis approach [17].

References