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Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 257 | 1p36.11 | NR0B2 | nuclear receptor subfamily 0 group B member 2 | 19 |
| Mouse | 260 | 4 66.25 cM | Nr0b2 | nuclear receptor subfamily 0, group B, member 2 | 19 |
| Rat | 260 | 5q36 | Nr0b2 | nuclear receptor subfamily 0, group B, member 2 | 17 |
| Previous and Unofficial Names |
| Small heterodimer partner | orphan nuclear receptor SHP | SHP-1 | nuclear receptor subfamily 0 |
| Database Links |
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| Alphafold | Q15466 (Hs), Q62227 (Mm), P97947 (Rn) |
| ChEMBL Target | CHEMBL5603 (Hs) |
| Ensembl Gene | ENSG00000131910 (Hs), ENSMUSG00000037583 (Mm), ENSRNOG00000007229 (Rn) |
| Entrez Gene | 8431 (Hs), 23957 (Mm), 117274 (Rn) |
| Human Protein Atlas | ENSG00000131910 (Hs) |
| KEGG Gene | hsa:8431 (Hs), mmu:23957 (Mm), rno:117274 (Rn) |
| OMIM | 604630 (Hs) |
| Pharos | Q15466 (Hs) |
| RefSeq Nucleotide | NM_021969 (Hs), NM_011850 (Mm), NM_057133 (Rn) |
| RefSeq Protein | NP_068804 (Hs), NP_035980 (Mm), NP_476474 (Rn) |
| UniProtKB | Q15466 (Hs), Q62227 (Mm), P97947 (Rn) |
| Wikipedia | NR0B2 (Hs) |
| Natural/Endogenous Ligands |
| Comments: Orphan |
| Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| SIN3A | Co-repressor | - | No | - | 1,12 | |
| HDAC3 | Co-repressor | No | No | No | 9 | |
| HDAC1 | Co-repressor | - | No | - | 1,3,9 | |
| EID1 | Co-repressor | Yes | No | - | 5 | |
| NCOR1 | Co-repressor | - | No | - | 1 | |
| NCOR2 | Co-repressor | - | No | - | 1,20 | |
| Main Co-regulators Comments | ||||||
| SHP mediates part of its repressive effect through recruitment of HDACs, suggesting that the physiological actions of SHP could be affected by HDAC inhibitors. Evidence indicates that SHP interacts with the Sin3A-Swi/Snf complex by direct interaction with Brm and mSin3A through its repression domain. | ||||||
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| CYP7A1 | Human | Repressed | Transient transfection | SHP represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. | 10,16 |
| SLC10A1 | Human | Repressed | Transient transfection, others | Solute carrier family 10 member 1(SLC10A1, or NTCP) is the principal hepatic bile acid transporter. SHP inhbits NTCP expression via direct interaction and inhibition of the RAR:RXR heterodimers. | 8 |
| ABCA1 | Human | Repressed | Transient transfection, others | SHP represses the expression of the ABCA1 gene which encodes the ATP-binding cassette transporter 1 via its interaction with the LXRalpha and beta, known transcriptional activator of ABCA1. | 4 |
| ACOX1 | Human | Repressed | Transient transfection, others | SHP differentially inhibits peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase | 11 |
| PCK1 | Human | Repressed | Transient transfection, others | SHP inhibits GR mediated transactivation of the PCK1 (PEPCK) promoter by competing with GR coactivators and by perturbing GR intranuclear localization. | 2 |
| Main Target Genes Comments | |||||
| All the target genes mentioned are also repressed likewise in all other species tested. | |||||
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| SHP is encoded by a 1.3 kb transcript expressed in liver and at lower levels in heart, adrenal gland, spleen and pancreas. It has been shown that the SHP promoter is activated by SF-1 (NR5A1) and its paralogue LRH1 (NR5A2). The mouse SHP promoter was shown to contains 5 SFREs that are all required for the activation by NR5A subfamily members. In addition, it was shown that SHP is coexpressed with SF1 in adrenal glands as well as with LRH1 in liver. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
| For a complete review on SHP see [6]. |
1. Bae Y, Kemper JK, Kemper B. (2004) Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol, 23 (2): 81-91. [PMID:15000748]
2. Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E. (2002) Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J Biol Chem, 277 (51): 49761-6. [PMID:12324453]
3. Boulias K, Talianidis I. (2004) Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression. Nucleic Acids Res, 32 (20): 6096-103. [PMID:15550569]
4. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J. (2002) The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol Endocrinol, 16 (9): 2065-76. [PMID:12198243]
5. Båvner A, Johansson L, Toresson G, Gustafsson JA, Treuter E. (2002) A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP. EMBO Rep, 3 (5): 478-84. [PMID:11964378]
6. Båvner A, Sanyal S, Gustafsson JA, Treuter E. (2005) Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol Metab, 16 (10): 478-88. [PMID:16275121]
7. Dawson MI, Xia Z, Jiang T, Ye M, Fontana JA, Farhana L, Patel B, Xue LP, Bhuiyan M, Pellicciari R et al.. (2008) Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity. J Med Chem, 51 (18): 5650-62. [PMID:18759424]
8. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ. (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology, 121 (1): 140-7. [PMID:11438503]
9. Gobinet J, Carascossa S, Cavaillès V, Vignon F, Nicolas JC, Jalaguier S. (2005) SHP represses transcriptional activity via recruitment of histone deacetylases. Biochemistry, 44 (16): 6312-20. [PMID:15835920]
10. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell, 6 (3): 517-26. [PMID:11030332]
11. Kassam A, Capone JP, Rachubinski RA. (2001) The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. Mol Cell Endocrinol, 176 (1-2): 49-56. [PMID:11369442]
12. Kemper JK, Kim H, Miao J, Bhalla S, Bae Y. (2004) Role of an mSin3A-Swi/Snf chromatin remodeling complex in the feedback repression of bile acid biosynthesis by SHP. Mol Cell Biol, 24 (17): 7707-19. [PMID:15314177]
13. Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, Schwarz M. (2002) Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell, 2 (6): 713-20. [PMID:12062084]
14. Lee HK, Lee YK, Park SH, Kim YS, Park SH, Lee JW, Kwon HB, Soh J, Moore DD, Choi HS. (1998) Structure and expression of the orphan nuclear receptor SHP gene. J Biol Chem, 273 (23): 14398-402. [PMID:9603951]
15. Lee YK, Parker KL, Choi HS, Moore DD. (1999) Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers. J Biol Chem, 274 (30): 20869-73. [PMID:10409629]
16. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ. (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell, 6 (3): 507-15. [PMID:11030331]
17. Masuda N, Yasumo H, Tamura T, Hashiguchi N, Furusawa T, Tsukamoto T, Sadano H, Osumi T. (1997) An orphan nuclear receptor lacking a zinc-finger DNA-binding domain: interaction with several nuclear receptors. Biochim Biophys Acta, 1350 (1): 27-32. [PMID:9003453]
18. Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, Kohama T, Yamagata K, Yang Q, Matsuzawa Y, Miki T, Seino S, Kim MY, Choi HS, Lee YK, Moore DD, Takeda J. (2001) Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci USA, 98 (2): 575-80. [PMID:11136233]
19. Seol W, Choi HS, Moore DD. (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science, 272 (5266): 1336-9. [PMID:8650544]
20. Seol W, Chung M, Moore DD. (1997) Novel receptor interaction and repression domains in the orphan receptor SHP. Mol Cell Biol, 17 (12): 7126-31. [PMID:9372944]
21. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M, Moore DD. (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell, 2 (6): 721-31. [PMID:12062085]
0B. DAX-like receptors: SHP. Last modified on 12/07/2018. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=636.
