Nuclear receptor-interacting protein 1 (NRIP1) also known as receptor-interacting protein 140 (RIP140) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''NRIP1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
Nuclear receptor interacting protein 1 (NRIP1) is a nuclear protein that specifically interacts with the hormone-dependent activation domain AF2 of
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
s. Also known as RIP140, this protein is a key regulator which modulates transcriptional activity of a variety of transcription factors, including the
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...
.
RIP140 has an important role in regulating lipid and glucose metabolism,
and regulates gene expression in metabolic tissues including heart,
skeletal muscle,
and liver.
A major role for RIP140 in adipose tissue is to block the expression of genes involved in energy dissipation and
mitochondrial
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
uncoupling, including
uncoupling protein 1
Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1) is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes ...
and
carnitine palmitoyltransferase 1b.
Estrogen-related receptor alpha
Estrogen-related receptor alpha (ERRα), also known as NR3B1 (nuclear receptor subfamily 3, group B, member 1), is a nuclear receptor that in humans is encoded by the ''ESRRA'' (Estrogen Related Receptor Alpha) gene. ERRα was originally cloned b ...
(ERRa) can activate RIP140 during adipogenesis, by means of directly binding to an estrogen receptor element/ERR element and indirectly through
Sp1 binding to the proximal promoter.
RIP140 suppresses the expression of mitochondrial proteins
succinate dehydrogenase
Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
complex b and
CoxVb and acts as a negative regulator of glucose uptake in mice.
Knockout studies
Knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
that completely lack the RIP140 molecule are lean and stay lean, even on a rich diet.
Knockout mice (females) are also infertile because they fail to
ovulate
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
.
Failure of ovulation in these mice is caused by lack of
cumulus
Cumulus clouds are clouds which have flat bases and are often described as "puffy", "cotton-like" or "fluffy" in appearance. Their name derives from the Latin ''cumulo-'', meaning ''heap'' or ''pile''. Cumulus clouds are low-level clouds, gener ...
expansion and altered expression of various genes, including
amphiregulin
Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the ''AREG'' gene. in humans.
Function
The protein encoded by this gene is a member of the epidermal growth fac ...
, in
ovarian follicles
An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with t ...
.
Clinical significance
RIP140 is part of the chain by which tumors can cause
cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart f ...
.
[ ]
Levels of RIP140 expression in various tissues varies during aging in mice, suggesting changes in metabolic function.
RIP140 is implicated in certain human disease processes. In morbid obesity, RIP140 levels are down-regulated in visceral adipose tissue.
In breast cancer, RIP140 is involved in regulation of E2F1, an oncogene which discriminates between luminal and basal types of tumours. RIP140 has an influence upon cancer phenotype and prognosis.
In addition, RIP140 has a role in inflammation, since it acts as a coactivator for
NFkappaB/
RelA
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene.
RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tran ...
-dependent
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s.
Interactions
NRIP1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
AHR
Ahr () is a river in Germany, a left tributary of the Rhine. Its source is at an elevation of approximately above sea level in Blankenheim in the Eifel, in the cellar of a timber-frame house near the castle of Blankenheim. After it crosses fro ...
,
*
CTBP1
C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the ''CTBP1'' gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.
Function
The CtBP1 protein was originally identified as a human prote ...
* CTBP2
C-terminal-binding protein 2 also known as CtBP2 is a protein that in humans is encoded by the ''CTBP2'' gene.
Function
The CtBPs - CtBP1 and CtBP2 in mammals - are among the best characterized transcriptional corepressors. They typically turn ...
,
* DAX1
DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) is a nuclear receptor protein that in humans is encoded by the ''NR0B1'' gene (nuclear receptor subfamily 0, group B, member 1). The ''NR0B1'' gene i ...
,[
* ]HDAC5
Histone deacetylase 5 is an enzyme that in humans is encoded by the ''HDAC5'' gene.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alte ...
,
* NR1B1,
* NR2B1,[
* ]NR3A1
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex ...
,
* NR3C1,
* NR5A1, and
* YWHAQ
14-3-3 protein theta is a protein that in humans is encoded by the ''YWHAQ'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins that mediate signal transduction by binding to phosphoserine-containing proteins. This highl ...
.
See also
* Transcription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are ...
References
Further reading
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External links
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*
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Nuclear receptor-interacting protein 1 (NRIP1)
{{Transcription coregulators
Gene expression
Transcription coregulators