NRIP1

Function

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 is a key regulator which modulates transcriptional activity of a variety of transcription factors, including the estrogen receptor.

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 uncoupling, including uncoupling protein 1 and carnitine palmitoyltransferase 1b.

Estrogen-related receptor alpha (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 complex b and CoxVb and acts as a negative regulator of glucose uptake in mice.

Knockout studies

Knockout mice 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. Failure of ovulation in these mice is caused by lack of cumulus expansion and altered expression of various genes, including amphiregulin, in ovarian follicles.

Clinical significance

RIP140 is part of the chain by which tumors can cause cachexia.

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-dependent cytokine gene expression. Lack of RIP140 leads to an inhibition of proinflammatory pathways in macrophages.

Interactions

NRIP1 has been shown to interact with:

• AHR,
• CTBP1
• CTBP2,
• DAX1,
• HDAC5,
• NR1B1,
• NR2B1,
• NR3A1,
• NR3C1,
• NR5A1, and
• YWHAQ.

References

References

1. (Sep 1995). "Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor". EMBO J.
2. (Apr 1998). "Localisation of receptor interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a gene-poor region of the human genome". Hum Genet.
3. "Entrez Gene: NRIP1 nuclear receptor interacting protein 1".
4. (2010). "Role of nuclear receptor corepressor RIP140 in metabolic syndrome.". Biochim Biophys Acta.
5. (2010). "Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function.". Cardiovasc Res.
6. (Sep 2007). "The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle". Cell Metab.
7. (Nov 2007). "The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor". Mol Endocrinol.
8. (July 2007). "Receptor interacting protein 140 regulates expression of uncoupling protein 1 in adipocytes through specific peroxisome proliferator activated receptor isoforms and estrogen-related receptor alpha". Mol. Endocrinol..
9. (Oct 2006). "RIP140 expression is stimulated by estrogen-related receptor alpha during adipogenesis.". J Biol Chem.
10. (2006). "Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes.". J Clin Invest.
11. (May 2004). "Nuclear receptor corepressor RIP140 regulates fat accumulation". Proc Natl Acad Sci U S A.
12. (Dec 2000). "The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility". Nat. Med..
13. (2005). "Multiple Signaling Defects in the Absence of RIP140 Impair Both Cumulus Expansion and Follicle Rupture". Endocrinology.
14. (2010). "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". Endocrinology.
15. (October 2010). "A common denominator of inflammations and fatty liver". Science Centric.
16. (April 2008). "Nuclear receptor cofactor receptor interacting protein 140 controls hepatic triglyceride metabolism during wasting in mice". Hepatology.
17. (2008). "Tissue-specific expression of receptor-interacting protein in aging mouse". Age (Dordr).
18. (2009). "RIP140 gene and protein expression levels are downregulated in visceral adipose tissue in human morbid obesity". Obes Surg.
19. (2010). "The transcriptional coregulator RIP140 represses E2F1 activity and discriminates breast cancer subtypes". Clin Cancer Res.
20. (2008). "Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene expression". Blood.
21. (Aug 1999). "Differential recruitment of coactivator RIP140 by Ah and estrogen receptors. Absence of a role for LXXLL motifs". J. Biol. Chem..
22. (Mar 2008). "TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints". Mol. Cell.
23. (2004). "Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition". Nucleic Acids Res..
24. (Jan 2004). "Suppressive effect of receptor-interacting protein 140 on coregulator binding to retinoic acid receptor complexes, histone-modifying enzyme activity, and gene activation". J. Biol. Chem..
25. (Feb 2003). "Effects of retinoid ligands on RIP140: molecular interaction with retinoid receptors and biological activity". Biochemistry.
26. (Nov 1996). "RIP-140 interacts with multiple nuclear receptors by means of two distinct sites". Mol. Cell. Biol..
27. (May 1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". J. Biol. Chem..
28. (Jun 2003). "Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140". Mol. Cell. Biol..
29. (Jun 1999). "Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids". J. Biol. Chem..
30. (August 2001). "RIP 140 modulates transcription of the steroidogenic acute regulatory protein gene through interactions with both SF-1 and DAX-1". Endocrinology.
31. (May 2003). "Characterization of receptor-interacting protein RIP140 in the regulation of SF-1 responsive target genes". Mol. Cell. Endocrinol..
32. (Apr 2001). "Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140". Mol. Endocrinol..