Table of Contents - *602490
External Links:
Genome
DNA
Protein
Gene Info
Variation
Animal Models
Cellular Pathways
| *602490 | ||||||||||||||||||||||||
| NUCLEAR RECEPTOR-INTERACTING PROTEIN 1; NRIP1 | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| RECEPTOR-INTERACTING PROTEIN 140; RIP140 | ||||||||||||||||||||||||
| HGNC Approved Gene Symbol: NRIP1 | ||||||||||||||||||||||||
| Cytogenetic location: 21q11.2-q21.1 Genomic coordinates (GRCh37): 21:16,333,555 - 16,437,125 (from NCBI) | ||||||||||||||||||||||||
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| Cloning | ||||||||||||||||||||||||
| Cavailles et al. (1995) identified receptor-interacting protein-140 (RIP140) by virtue of its direct association with a transcriptional activation domain of estrogen receptor (ESR; 133430) in the presence of estrogen. Using the ligand-binding domain of Tr2 (NR2C1; 601529) as bait in a yeast 2-hybrid screen of an embryonic mouse cDNA library, Lee et al. (1998) cloned Rip140. Like the 1,158-amino acid human protein, the deduced mouse protein contains 9 LxxLL signature motifs. Northern blot analysis detected an 8-kb Rip140 transcript in all adult mouse tissues examined and in embryonic day-12.5 placenta and embryos. | ||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||
| L'Horset et al. (1996) identified 2 binding sites in RIP140 that interacted with the ligand-binding domain of ESR both in solution and when the receptor was bound to DNA. Both sites independently interacted with other nuclear receptors, including thyroid hormone receptors (e.g., THRB; 190160) and retinoic acid receptors (e.g., RARB; 180220), but their binding properties were not identical. These interactions were enhanced by receptor agonists, but not by antagonists, and in vitro binding of RIP140 to a number of mutant receptors correlated with their ability to stimulate transcription in vivo. When RIP140 was fused to heterologous DNA-binding domains, it could stimulate transcription of reporter genes in both yeast and mammalian cells. L'Horset et al. (1996) concluded that RIP140 functions as a bridge between receptors and the basal transcription machinery and thereby stimulates transcription of target genes. By mutation analysis, Lee et al. (1998) determined that the LxxLL motifs of mouse Rip140 interacted with the activation function-2 region of Tr2. Coimmunoprecipitation experiments detected interaction between the 2 proteins in cell extracts. Rip140 repressed binding of Tr2 to target DNA and suppressed induction of retinoic acid (RA) receptor (see 180240) by RA in a dose-dependent manner. In the presence of Rip140, Tr2 translocated into the nucleus. Using yeast 2-hybrid analysis, protein pull-down assays, and coimmunoprecipitation analysis, Sugawara et al. (2001) showed that RIP140 interacted with SF1 (NR5A1; 184757) and DAX1 (NR0B1; 300473), which control expression of STAR (600617), a regulator of intramitochondrial cholesterol transport. Using reporter gene constructs, they showed that RIP140 inhibited STAR expression in an SF1-dependent manner. RIP140 and DAX1 inhibited cAMP-stimulated activity of an SF1 response element synergistically. White et al. (2008) reviewed the fundamental role of RIP140 in normal cellular function, as well as in pathology of metabolic diseases. They stated that RIP140 can act as a transcriptional repressor or activator depending upon the transcriptional factors with which it interacts. The repressive function of RIP140 can be modulated posttranslationally by phosphorylation, arginine methylation, acetylation, and conjugation of lys613 with pyridoxal 5-prime-phosphate. | ||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||
| By fluorescence in situ hybridization, Cavailles et al. (1995) mapped the RIP140 gene to chromosome 21q11. Katsanis et al. (1998) used hybrids, YACs, and PACs to place the RIP140 gene on the physical map of chromosome 21; 21q11 is a gene-poor region. | ||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||
| White et al. (2000) found that Rip140-null mice were viable but smaller than their wildtype littermates. Female mice were completely infertile due to complete failure of mature follicles to release oocytes at ovulation. In contrast, luteinization proceeded normally in Rip140-null mice, resulting in a phenotype similar to luteinized unruptured follicle syndrome in women. Leonardsson et al. (2004) found that Rip140 -/- mice were lean, resisted high-fat diet-induced obesity and hepatic steatosis, and had increased oxygen consumption. Although adipogenesis was unaffected, expression of certain lipogenic enzymes was reduced. In contrast, genes involved in energy dissipation and mitochondrial uncoupling, including uncoupling protein-1 (UCP1; 113730), were markedly increased. Leonardsson et al. (2004) concluded that RIP140 regulates the expression of genes involved in energy homeostasis. | ||||||||||||||||||||||||
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