NRIP1 (nuclear receptor interacting protein 1)

2018-04-01 Vincent Cavaillès , Marion Lapierre Affiliation

Identity

HGNC

NRIP1

LOCATION

21q11.2

LOCUSID

8204

ALIAS

CAKUT3,RIP140

FUSION GENES

Show Gene Fusions

Abstract

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

DNA/RNA

Description

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

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.

Pseudogene

None known.

Proteins

Description

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.

Expression

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.

Localisation

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

Function

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.

Homology

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

Mutations

Note

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

Note

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

Note

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

Note

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

Infertility

Note

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.

Entity name

Gastro-intestinal homeostasis and tumorigenesis

Note

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.

Entity name

Cognition and neural cells

Note

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.

Entity name

Aging and longevity

Note

The deletion of NRIP1 in female mice can significantly extend longevity compared to wild-type females

Entity name

Immunity and inflammation

Note

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.

Bibliography

Pubmed ID	Last Year	Title	Authors
16391242	2006	Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin signalling.	Augereau P et al
26492163	2015	Suppressing NRIP1 inhibits growth of breast cancer cells in vitro and in vivo.	Aziz MH et al
27614112	2016	The nuclear cofactor receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation.	Blondrath K et al
16131398	2005	Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis.	Caballero V et al
17013392	2006	Genome-wide analysis of estrogen receptor binding sites.	Carroll JS et al
7641693	1995	Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor.	Cavaillès V et al
26406163	2015	Amelioration of palmitate-induced metabolic dysfunction in L6 muscle cells expressing low levels of receptor-interacting protein 140.	Constantinescu S et al
28656645	2017	Regulation of Nuclear Receptor Interacting Protein 1 (NRIP1) Gene Expression in Response to Weight Loss and Exercise in Humans.	De Marinis Y et al
23885094	2013	Negative regulation of estrogen signaling by ERβ and RIP140 in ovarian cancer cells.	Docquier A et al
21906262	2012	Cognitive impairments in adult mice with constitutive inactivation of RIP140 gene expression.	Duclot F et al
22389706	2012	Absence of RIP140 reveals a pathway regulating glut4-dependent glucose uptake in oxidative skeletal muscle through UCP1-mediated activation of AMPK.	Fritah A et al
16213843	2005	Multilocus 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
15976005	2005	Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells.	Graham JD et al
19862326	2009	Retinoic acid mediates long-paced oscillations in retinoid receptor activity: evidence for a potential role for RIP140.	Heim KC et al
17880687	2007	Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.	Heim KC et al
17684114	2007	The 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
21285396	2011	Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production.	Ho PC et al
22934550	2012	Biological activities of receptor-interacting protein 140 in adipocytes and metabolic diseases.	Ho PC et al
28393222	2017	Overexpression of RIP140 suppresses the malignant potential of hepatocellular carcinoma by inhibiting NF‑κB‑mediated alternative polarization of macrophages.	Hu YC et al
19216533	2009	Lysine methylation of nuclear co-repressor receptor interacting protein 140.	Huq MD et al
24698981	2014	NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.	Izzo A et al
28414308	2017	Complex regulation of LCoR signaling in breast cancer cells.	Jalaguier S et al
25701715	2015	RIP140 as a novel therapeutic target in the treatment of atherosclerosis.	Karasawa T et al
11467847	2001	Transcriptional activation of the nuclear receptor corepressor RIP140 by retinoic acid: a potential negative-feedback regulatory mechanism.	Kerley JS et al
26116758	2015	The emerging role of the transcriptional coregulator RIP140 in solid tumors.	Lapierre M et al
26213846	2015	NOP14 suppresses breast cancer progression by inhibiting NRIP1/Wnt/β-catenin pathway.	Lei JJ et al
15155905	2004	Nuclear receptor corepressor RIP140 regulates fat accumulation.	Leonardsson G et al
12040012	2002	Expression 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
27929078	2016	Gut microbiota from metabolic disease-resistant, macrophage-specific RIP140 knockdown mice improves metabolic phenotype and gastrointestinal integrity.	Lin YW et al
24969109	2014	Reducing RIP140 expression in macrophage alters ATM infiltration, facilitates white adipose tissue browning, and prevents high-fat diet-induced insulin resistance.	Liu PS et al
27708240	2016	Overexpression and potential roles of NRIP1 in psoriasis.	Luan C et al
18288993	2008	Post-translational modifications of nuclear co-repressor RIP140: a therapeutic target for metabolic diseases.	Mostaqul Huq MD et al
23742741	2013	Distinct functions for RIP140 in development, inflammation, and metabolism.	Nautiyal J et al
16923809	2006	RIP140 expression is stimulated by estrogen-related receptor alpha during adipogenesis.	Nichol D et al
16374519	2006	Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes.	Powelka AM et al
18211901	2008	SUMOylation modulates the transcription repressor function of RIP140.	Rytinki MM et al
17767910	2007	The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle.	Seth A et al
29340045	2017	RIP140 and LCoR expression in gastrointestinal cancers.	Triki M et al
28740336	2017	Expression and role of nuclear receptor coregulators in colorectal cancer.	Triki M et al
29285256	2017	Investigation of RIP140 and LCoR as independent markers for poor prognosis in cervical cancer.	Vattai A et al
11509661	2001	Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP.	Vo N et al
29346516	2018	Deletion of Nrip1 Extends Female Mice Longevity, Increases Autophagy, and Delays Cell Senescence.	Wang J et al
11006275	2000	Receptor-interacting protein 140 directly recruits histone deacetylases for gene silencing.	Wei LN et al
15632153	2005	Limiting effects of RIP140 in estrogen signaling: potential mediation of anti-estrogenic effects of retinoic acid.	White KA et al
11100122	2000	The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility.	White R et al
18023280	2008	Role of RIP140 in metabolic tissues: connections to disease.	White R et al
29541202	2018	Synergistic effect of receptor-interacting protein 140 and simvastatin on the inhibition of proliferation and survival of hepatocellular carcinoma cells.	Xia K et al
22956256	2013	RIP140 is associated with subclinical inflammation in type 2 diabetic patients.	Xue J et al
28586037	2017	Transcriptional co-regulator RIP140: An important mediator of the inflammatory response and its associated diseases (Review).	Yi ZJ et al
28250757	2017	Correlation 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

Variants:

dbSNP: 8204
ClinVar: 8204
TCGA: ENSG00000180530
COSMIC: NRIP1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000180530	ENST00000318948	P48552
ENSG00000180530	ENST00000400199	P48552
ENSG00000180530	ENST00000400202	P48552
ENSG00000180530	ENST00000411932	C9J130
ENSG00000180530	ENST00000638122	A0A1B0GUG9

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Circadian Clock	REACTOME	R-HSA-400253
BMAL1:CLOCK,NPAS2 activates circadian gene expression	REACTOME	R-HSA-1368108
RORA activates gene expression	REACTOME	R-HSA-1368082

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
23774759	2013	Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.	39
16439465	2006	Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes.	37
18660489	2008	Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.	26
14736873	2004	Characterization of four autonomous repression domains in the corepressor receptor interacting protein 140.	24
20453000	2010	A Large-scale genetic association study of esophageal adenocarcinoma risk.	23
12773562	2003	Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140.	22
18211901	2008	SUMOylation modulates the transcription repressor function of RIP140.	21
20200160	2010	Down-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
20410059	2010	The transcriptional coregulator RIP140 represses E2F1 activity and discriminates breast cancer subtypes.	20

Citation

Vincent Cavaillès ; Marion Lapierre

NRIP1 (nuclear receptor interacting protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2018-04-01

Online version: http://atlasgeneticsoncology.org/gene/44067/nrip1

Historical Card

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

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