NRIP1 (nuclear receptor interacting protein 1)

2018-04-01   Vincent Cavaillès , Marion Lapierre 




Review on NRIP1, with data on DNA, on the protein encoded, and where the gene is implicated.


Atlas Image


The gene encompasses approximately 100 Kb and may contain up to 7 exons. The entire protein-coding region is contained within the last exon.


Transcription is complex. Alternative spliced transcripts containing distinct combinations of 5 non-coding exons occur. Alternative promoters have been described and are proposed to mediate tissue specific expression of NRIP1. NRIP1 is induced by a number of hormone nuclear receptors including the receptors for estrogen, retinoic acid, androgen, progestins, vitamin D3, peroxisome proliferators-activated receptor-alpha (PPARalpha) and estrogen related receptor-alpha (ERRalpha). NRIP1 gene transcription is also induced by E2F transcription factors.
NRIP1 mRNA is widely expressed in various tissues and cell types.


None known.


Atlas Image


NRIP1 consists of 1158 amino acids. NRIP1 contains ten LXXLL nuclear receptor interaction motifs and four transcriptional repression domains (RD 1-4). NRIP1 also contains four c-terminal binding protein (CtBP) interaction motifs. NRIP1 activity is regulated by a variety of posttranslational modifications including acetylation, methylation, phosphorylation, sumoylation, and pyridoxal-phosphate (PLP) conjugation.


NRIP1 is expressed at low levels in most tissues and is induced in response to hormonal signals. NRIP1 is highly expressed in metabolic and reproductive organs and tissues including the liver, adipose tissue, skeletal muscle, ovary and endometrium.


NRIP1 is mainly expressed in the nucleus and contains two putative nuclear localization signals (NLS).


NRIP1 is a co-repressor of a large number of nuclear receptors. NRIP1 interacts preferentially with ligand-bound nuclear receptors and inhibits transactivation by recruitment of histone deacetylases and CtBP. Knockout mice studies revealed that NRIP1 has a physiologic role in energy homeostasis, muscle metabolism, adipocyte and hepatocyte function, mitochondrial activity, inflammation, reproduction and cognition. Data suggest that these roles are mediated by NRIP1 repression of nuclear receptor mediated gene expression including gene expression mediated by the estrogen receptor, liver X receptor, PPARs, steroidogenic factor 1 (SF1) and ERR.
NRIP1 has been shown to regulate retinoic acid mediated differentiation and growth suppression of human embryonal carcinoma cells and the proliferation of breast cancer cells in vitro. A potential role for NRIP1 in cancer cachexia has been suggested. Interestingly, NRIP1 also regulates the activity of other transcription factors including E2Fs and NFKB.
The fact that NRIP1 expression can be regulated by multiple transcription factors and especially nuclear receptors and their ligands and that NRIP1 can inhibits the activity of multiple nuclear receptors implies a potential role in the biology of hormone-dependent cancers. This role in cancer biology which has recently been described in colon, stomach, breast and cervix.


NRIP1 is highly conserved throughout vertebrates. There is only a single isoform in humans and mice.



Several synonymous and non-synonymous SNPs have been identified. To date no somatic tumor mutations have been noted.
- Arg448Gly has been associated with endometriosis.
- Gly75Gly has been associated with male infertility.

Implicated in

Entity name
Hormone dependent cancers
In a variety of cancer cell culture systems mouse models and tissue arrays, NRIP1 has been shown to regulate the activity of a number of nuclear receptors involved in hormone-dependent cancers including estrogen, retinoid, progesterone and androgen receptors. Moreover, NRIP1 mRNA is finely regulated during cell cycle progression, modulating cell growth and apoptosis. Finally, NRIP1 overexpression is associated with a significantly shorter overall survival of cervical cancer patients and discriminates luminal breast cancers
Entity name
Cancer cachexia
NRIP1 was induced in livers of starved, septic, and tumor-bearing mice. Liver-specific knockdown of NRIP1 led to increased hepatic TG release and alleviated hepatic steatosis in tumor-bearing, cachectic animals. NRIP1 was found to control the expression of lipid-metabolizing genes in liver.
Entity name
Obesity and metabolic disorders
NRIP1 knockout mice are lean and are resistant to high-fat diet induced obesity. NRIP1 regulates genes involved in energy homeostasis in metabolic organs. Moreover, low level of NRIP1 restores the rates of fatty-acids uptake in the basal state, in part via a reduction in upstream insulin signaling. In addition, increased NRIP1 level may be closely associated with inflammation and disorder of lipid and glucose metabolism in diabetic patients. In addition, detectable serum NRIP1 protein level changes is associated with weight loss in humans.
Entity name
Female NRIP1 knockout mice are infertile due to a defect in ovulation. Also the above-mentioned SNPs have been proposed to be associated with endometriosis and male fertility.
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Gastro-intestinal homeostasis and tumorigenesis
Using molecular and cellular approaches, transgenic mouse models and human colorectal biopsies, NRIP1 has been shown to inhibit cell proliferation and apoptosis in the murine intestinal epithelium. In addition, NRIP1 exerts a negative control on Wnt/beta-catenin signaling by positively regulating the expression of the tumor suppressor gene APC. High NRIP1 expression is associated with a significantly longer overall survival of colorectal cancer patients. Interestingly, whereas NRIP1 expression tends to decrease in colorectal cancers as compared to adjacent normal tissues, an increase of its expression was noticed in gastric cancer as compared to normal stomach.
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Cognition and neural cells
The NRIP1 gene depletion in mice results in learning and memory deficits as well as stress response, bringing to light a major role for this transcriptional coregulator in the neurophysiological developmental mechanisms underlying cognitive functions. In addition, NRIP1 plays a relevant role in Down syndrome mitochondrial dysfunction. Moreover, NRIP1 expression increases during neural differentiation of human embryonic stem cells and is negatively correlated with stem cell markers Oct4 and Sox2 during early stages of neural differentiation.
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Aging and longevity
The deletion of NRIP1 in female mice can significantly extend longevity compared to wild-type females
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Immunity and inflammation
Overexpression of NRIP1 in macrophages results in M1u001elike polarization and expansion during the inflammatory response. Conversely, decreased expression of NRIP1 in macrophages reduces the number of M1u001elike macrophages and increases the number of alternatively polarized cells, which collectively promote endotoxin tolerance and relieve inflammation.


Pubmed IDLast YearTitleAuthors
163912422006Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin signalling.Augereau P et al
264921632015Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo.Aziz MH et al
276141122016The nuclear cofactor receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation.Blondrath K et al
161313982005Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis.Caballero V et al
170133922006Genome-wide analysis of estrogen receptor binding sites.Carroll JS et al
76416931995Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor.Cavaillès V et al
264061632015Amelioration of palmitate-induced metabolic dysfunction in L6 muscle cells expressing low levels of receptor-interacting protein 140.Constantinescu S et al
286566452017Regulation of Nuclear Receptor Interacting Protein 1 (NRIP1) Gene Expression in Response to Weight Loss and Exercise in Humans.De Marinis Y et al
238850942013Negative regulation of estrogen signaling by ERβ and RIP140 in ovarian cancer cells.Docquier A et al
219062622012Cognitive impairments in adult mice with constitutive inactivation of RIP140 gene expression.Duclot F et al
223897062012Absence of RIP140 reveals a pathway regulating glut4-dependent glucose uptake in oxidative skeletal muscle through UCP1-mediated activation of AMPK.Fritah A et al
162138432005Multilocus analyses of estrogen-related genes reveal involvement of the ESR1 gene in male infertility and the polygenic nature of the pathology.Galan JJ et al
159760052005Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells.Graham JD et al
198623262009Retinoic acid mediates long-paced oscillations in retinoid receptor activity: evidence for a potential role for RIP140.Heim KC et al
178806872007Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.Heim KC et al
176841142007The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor.Herzog B et al
212853962011Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production.Ho PC et al
229345502012Biological activities of receptor-interacting protein 140 in adipocytes and metabolic diseases.Ho PC et al
283932222017Overexpression of RIP140 suppresses the malignant potential of hepatocellular carcinoma by inhibiting NF‑κB‑mediated alternative polarization of macrophages.Hu YC et al
192165332009Lysine methylation of nuclear co-repressor receptor interacting protein 140.Huq MD et al
246989812014NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.Izzo A et al
284143082017Complex regulation of LCoR signaling in breast cancer cells.Jalaguier S et al
257017152015RIP140 as a novel therapeutic target in the treatment of atherosclerosis.Karasawa T et al
114678472001Transcriptional activation of the nuclear receptor corepressor RIP140 by retinoic acid: a potential negative-feedback regulatory mechanism.Kerley JS et al
261167582015The emerging role of the transcriptional coregulator RIP140 in solid tumors.Lapierre M et al
262138462015NOP14 suppresses breast cancer progression by inhibiting NRIP1/Wnt/β-catenin pathway.Lei JJ et al
151559052004Nuclear receptor corepressor RIP140 regulates fat accumulation.Leonardsson G et al
120400122002Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation.Lin R et al
279290782016Gut microbiota from metabolic disease-resistant, macrophage-specific RIP140 knockdown mice improves metabolic phenotype and gastrointestinal integrity.Lin YW et al
249691092014Reducing RIP140 expression in macrophage alters ATM infiltration, facilitates white adipose tissue browning, and prevents high-fat diet-induced insulin resistance.Liu PS et al
277082402016Overexpression and potential roles of NRIP1 in psoriasis.Luan C et al
182889932008Post-translational modifications of nuclear co-repressor RIP140: a therapeutic target for metabolic diseases.Mostaqul Huq MD et al
237427412013Distinct functions for RIP140 in development, inflammation, and metabolism.Nautiyal J et al
169238092006RIP140 expression is stimulated by estrogen-related receptor alpha during adipogenesis.Nichol D et al
163745192006Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes.Powelka AM et al
182119012008SUMOylation modulates the transcription repressor function of RIP140.Rytinki MM et al
177679102007The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle.Seth A et al
293400452017RIP140 and LCoR expression in gastrointestinal cancers.Triki M et al
287403362017Expression and role of nuclear receptor coregulators in colorectal cancer.Triki M et al
292852562017Investigation of RIP140 and LCoR as independent markers for poor prognosis in cervical cancer.Vattai A et al
115096612001Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP.Vo N et al
293465162018Deletion of Nrip1 Extends Female Mice Longevity, Increases Autophagy, and Delays Cell Senescence.Wang J et al
110062752000Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing.Wei LN et al
156321532005Limiting effects of RIP140 in estrogen signaling: potential mediation of anti-estrogenic effects of retinoic acid.White KA et al
111001222000The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility.White R et al
180232802008Role of RIP140 in metabolic tissues: connections to disease.White R et al
295412022018Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells.Xia K et al
229562562013RIP140 is associated with subclinical inflammation in type 2 diabetic patients.Xue J et al
285860372017Transcriptional co-regulator RIP140: An important mediator of the inflammatory response and its associated diseases (Review).Yi ZJ et al
282507572017Correlation between receptor-interacting protein 140 expression and directed differentiation of human embryonic stem cells into neural stem cells.Zhao ZR et al

Other Information

Locus ID:

NCBI: 8204
MIM: 602490
HGNC: 8001
Ensembl: ENSG00000180530


dbSNP: 8204
ClinVar: 8204
TCGA: ENSG00000180530


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Circadian ClockREACTOMER-HSA-400253
BMAL1:CLOCK,NPAS2 activates circadian gene expressionREACTOMER-HSA-1368108
RORA activates gene expressionREACTOMER-HSA-1368082

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
237747592013Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.39
164394652006Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes.37
186604892008Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.26
147368732004Characterization of four autonomous repression domains in the corepressor receptor interacting protein 140.24
204530002010A Large-scale genetic association study of esophageal adenocarcinoma risk.23
127735622003Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140.22
182119012008SUMOylation modulates the transcription repressor function of RIP140.21
202001602010Down-regulation of PROS1 gene expression by 17beta-estradiol via estrogen receptor alpha (ERalpha)-Sp1 interaction recruiting receptor-interacting protein 140 and the corepressor-HDAC3 complex.21
204100592010The transcriptional coregulator RIP140 represses E2F1 activity and discriminates breast cancer subtypes.20


Vincent Cavaillès ; Marion Lapierre

NRIP1 (nuclear receptor interacting protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2018-04-01

Online version:

Historical Card

2009-12-01 NRIP1 (nuclear receptor interacting protein 1) by  Michael J Spinella 

Department of Pharmacology, Dartmouth Medical School, 7650 Remsen, Hanover NH 03755, USA