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Gene Review

NR0B2  -  nuclear receptor subfamily 0, group B,...

Homo sapiens

Synonyms: Nuclear receptor subfamily 0 group B member 2, Orphan nuclear receptor SHP, SHP, SHP1, Small heterodimer partner
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Disease relevance of NR0B2

  • Several recently described SHP mutations associated with moderate obesity in humans block the inhibition of ERRgamma activity [1].
  • Finally, we found that a four-nucleotide deletion (-195CT-GAdel) in the hSHP promoter, which is reported to be associated with altered body weight and insulin secretion in human, coincides with the SRE1 [2].
  • In transient transfection assays, SHP inhibited 4-OHT-stimulated reporter gene activity from an estrogen response element (ERE) in ER-positive RL95-2 but not in HEC-1A human endometrial carcinoma cells transfected with ER(alpha) or ERbeta [3].
  • We examined the relation between genetic variation in SHP and birth weight, adiposity, and insulin levels in three independent populations [4].
  • In this paper, we summarize recent studies on the expression and regulation of SHP-1 protein and its pathological function in the development of lymphoma, leukemia and other cancers [5].

High impact information on NR0B2

  • Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes [6].
  • These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese [6].
  • FcalphaRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVAD-fmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration [7].
  • Our results suggest that SHP mediates recruitment of mSin3A-Swi/Snf to the CYP7A1 promoter, resulting in chromatin remodeling and gene repression, which may also be a mechanism for the repression by SHP of genes activated by many nuclear receptors [8].
  • Bile acid-induced recruitment of mSin3A/Brm, chromatin remodeling, and concomitant repression of endogenous CYP7A1 expression were impaired when SHP expression was inhibited by SHP small interfering RNA [8].

Chemical compound and disease context of NR0B2

  • SHP-1 has been proposed as a candidate tumor suppressor gene in lymphoma, leukemia and other cancers, as it functions as an antagonist to the growth-promoting and oncogenic potentials of tyrosine kinase [5].
  • The aim of this prospective, follow-up study was to examine the influence of overt hypothyroidism (OHP) and subclinical (SHP), before and during thyroxine (T4) treatment, on lipoprotein(a) [Lp(a)], other lipoproteins, and apolipoproteins [9].
  • Treatment of calcitriol has a beneficial effect on renal anemia in ESRD patients with SHP [10].

Biological context of NR0B2

  • Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors [11].
  • Overall, these results identify a new autoregulatory loop controlling SHP gene expression and significantly extend the potential functional roles of the three ERRs [1].
  • In transfection assays, SHP inhibits the expression of an artificial reporter driven by an LXR-response element and represses the transcriptional activation by LXR of the human ATP-binding cassette transporter 1 (ABCA1) promoter [12].
  • The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c [13].
  • While the mechanistic basis of these interactions has remained enigmatic, SHP has been suggested to inhibit nuclear receptor activation by at least three alternatives; inhibition of DNA binding via dimerization, direct antagonism of coactivator function via competition, and possibly transrepression via recruitment of putative corepressors [14].

Anatomical context of NR0B2


Associations of NR0B2 with chemical compounds

  • As with other SHP targets, this interaction is dependent on the AF-2 coactivator-binding site of ERRgamma and the previously described N-terminal receptor interaction domain of SHP [1].
  • Overexpression of the farnesoid X receptor-inducible transcriptional repressor small heterodimer partner also suppressed the GR/dexamethasone-activation of the hNTCP promoter [18].
  • The FXR antagonist guggulsterone blocked the induction of SHP by androsterone in AML-12 cells [15].
  • We now show that SHP binds directly to estrogen receptors via LXXLL-related motifs [14].
  • Although no conventional receptor function has yet been identified, SHP has been proposed to act as a negative regulator of nuclear receptor signaling pathways, because it interacts with and inhibits DNA binding and transcriptional activity of various nonsteroid receptors, including thyroid hormone and retinoid receptors [19].

Physical interactions of NR0B2

  • The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity [12].
  • We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs [20].
  • In contrast, SHP interacts with ERbeta independent of ligand and reduces its ability to activate transcription by only 50% [21].
  • SHP specifically targets the ligand-regulated activation domain AF-2 and competes for binding of coactivators such as TIF2 [19].
  • Interestingly, yeast two-hybrid and glutathione-S-transferase pull-down assays demonstrated that wild-type and SHP Delta128-139 have similar abilities to interact with estrogen receptor-related receptor-gamma, hepatocyte nuclear factor 4alpha, and constitutive androstane receptor [22].

Regulatory relationships of NR0B2

  • We have found that the SHP promoter is also activated by the estrogen receptor-related receptor gamma (ERRgamma) but not the related ERRalpha and ERRbeta isoforms [1].
  • A negative nuclear receptor, small heterodimer partner markedly inhibited transactivation of CYP8B1 by HNF4alpha [23].
  • We demonstrated that SHP inhibited up to 97% of AR-induced activity [24].
  • Instead, SHP may either inhibit recruitment of other coactivators by GRIP1 or actively recruit corepressors directly to the CAR/RXR/PBRU complex [25].
  • Thus, SHP appears to be an important modulatory component to regulate the transcriptional activities of NF kappa B in oxLDL-treated, resting macrophage cells [17].

Other interactions of NR0B2


Analytical, diagnostic and therapeutic context of NR0B2


  1. Differential regulation of the orphan nuclear receptor small heterodimer partner (SHP) gene promoter by orphan nuclear receptor ERR isoforms. Sanyal, S., Kim, J.Y., Kim, H.J., Takeda, J., Lee, Y.K., Moore, D.D., Choi, H.S. J. Biol. Chem. (2002) [Pubmed]
  2. Differential regulation of human and mouse orphan nuclear receptor small heterodimer partner promoter by sterol regulatory element binding protein-1. Kim, H.J., Kim, J.Y., Kim, J.Y., Park, S.K., Seo, J.H., Kim, J.B., Lee, I.K., Kim, K.S., Choi, H.S. J. Biol. Chem. (2004) [Pubmed]
  3. The agonist activity of tamoxifen is inhibited by the short heterodimer partner orphan nuclear receptor in human endometrial cancer cells. Klinge, C.M., Jernigan, S.C., Risinger, K.E. Endocrinology (2002) [Pubmed]
  4. Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: mutational analysis and association studies in multiple populations. Hung, C.C., Farooqi, I.S., Ong, K., Luan, J., Keogh, J.M., Pembrey, M., Yeo, G.S., Dunger, D., Wareham, N.J., O' Rahilly, S. Diabetes (2003) [Pubmed]
  5. The function of the protein tyrosine phosphatase SHP-1 in cancer. Wu, C., Sun, M., Liu, L., Zhou, G.W. Gene (2003) [Pubmed]
  6. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. 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, M.Y., Choi, H.S., Lee, Y.K., Moore, D.D., Takeda, J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  7. IgA Fc receptor I signals apoptosis through the FcR{gamma} ITAM and affects tumor growth. Kanamaru, Y., Tamouza, H., Pfirsch, S., El Mehdi, D., Gu??rin-Marchand, C., Pretolani, M., Blank, U., Monteiro, R.C. Blood (2007) [Pubmed]
  8. Role of an mSin3A-Swi/Snf chromatin remodeling complex in the feedback repression of bile acid biosynthesis by SHP. Kemper, J.K., Kim, H., Miao, J., Bhalla, S., Bae, Y. Mol. Cell. Biol. (2004) [Pubmed]
  9. Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment. Tzotzas, T., Krassas, G.E., Konstantinidis, T., Bougoulia, M. Thyroid (2000) [Pubmed]
  10. Improved anemia and reduced erythropoietin need by medical or surgical intervention of secondary hyperparathyroidism in hemodialysis patients. Lin, C.L., Hung, C.C., Yang, C.T., Huang, C.C. Renal failure. (2004) [Pubmed]
  11. Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. Nishizawa, H., Yamagata, K., Shimomura, I., Takahashi, M., Kuriyama, H., Kishida, K., Hotta, K., Nagaretani, H., Maeda, N., Matsuda, M., Kihara, S., Nakamura, T., Nishigori, H., Tomura, H., Moore, D.D., Takeda, J., Funahashi, T., Matsuzawa, Y. J. Biol. Chem. (2002) [Pubmed]
  12. The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Brendel, C., Schoonjans, K., Botrugno, O.A., Treuter, E., Auwerx, J. Mol. Endocrinol. (2002) [Pubmed]
  13. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Watanabe, M., Houten, S.M., Mataki, C., Christoffolete, M.A., Kim, B.W., Sato, H., Messaddeq, N., Harney, J.W., Ezaki, O., Kodama, T., Schoonjans, K., Bianco, A.C., Auwerx, J. Nature (2006) [Pubmed]
  14. The orphan nuclear receptor SHP utilizes conserved LXXLL-related motifs for interactions with ligand-activated estrogen receptors. Johansson, L., Båvner, A., Thomsen, J.S., Färnegårdh, M., Gustafsson, J.A., Treuter, E. Mol. Cell. Biol. (2000) [Pubmed]
  15. The nuclear hormone receptor farnesoid X receptor (FXR) is activated by androsterone. Wang, S., Lai, K., Moy, F.J., Bhat, A., Hartman, H.B., Evans, M.J. Endocrinology (2006) [Pubmed]
  16. VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Chignard, N., Mergey, M., Barbu, V., Finzi, L., Tiret, E., Paul, A., Housset, C. Hepatology (2005) [Pubmed]
  17. The orphan nuclear receptor small heterodimer partner as a novel coregulator of nuclear factor-kappa b in oxidized low density lipoprotein-treated macrophage cell line RAW 264.7. Kim, Y.S., Han, C.Y., Kim, S.W., Kim, J.H., Lee, S.K., Jung, D.J., Park, S.Y., Kang, H., Choi, H.S., Lee, J.W., Pak, Y.K. J. Biol. Chem. (2001) [Pubmed]
  18. The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism. Eloranta, J.J., Jung, D., Kullak-Ublick, G.A. Mol. Endocrinol. (2006) [Pubmed]
  19. The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ERalpha and ERbeta. Johansson, L., Thomsen, J.S., Damdimopoulos, A.E., Spyrou, G., Gustafsson, J.A., Treuter, E. J. Biol. Chem. (1999) [Pubmed]
  20. Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Ortlund, E.A., Lee, Y., Solomon, I.H., Hager, J.M., Safi, R., Choi, Y., Guan, Z., Tripathy, A., Raetz, C.R., McDonnell, D.P., Moore, D.D., Redinbo, M.R. Nat. Struct. Mol. Biol. (2005) [Pubmed]
  21. Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner). Seol, W., Hanstein, B., Brown, M., Moore, D.D. Mol. Endocrinol. (1998) [Pubmed]
  22. Differential role of the loop region between helices H6 and H7 within the orphan nuclear receptors small heterodimer partner and DAX-1. Park, Y.Y., Kim, H.J., Kim, J.Y., Kim, M.Y., Song, K.H., Cheol Park, K., Yu, K.Y., Shong, M., Kim, K.H., Choi, H.S. Mol. Endocrinol. (2004) [Pubmed]
  23. Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression. Zhang, M., Chiang, J.Y. J. Biol. Chem. (2001) [Pubmed]
  24. Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP. Gobinet, J., Auzou, G., Nicolas, J.C., Sultan, C., Jalaguier, S. Biochemistry (2001) [Pubmed]
  25. Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). Bae, Y., Kemper, J.K., Kemper, B. DNA Cell Biol. (2004) [Pubmed]
  26. Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis. Honda, A., Salen, G., Matsuzaki, Y., Batta, A.K., Xu, G., Hirayama, T., Tint, G.S., Doy, M., Shefer, S. J. Lipid Res. (2005) [Pubmed]
  27. The orphan nuclear receptor SHP is involved in monocytic differentiation, and its expression is increased by c-Jun. Choi, Y.H., Park, M.J., Kim, K.W., Lee, H.C., Choi, Y.H., Cheong, J. J. Leukoc. Biol. (2004) [Pubmed]
  28. Mutation analysis of NR0B2 among 1545 Danish men identifies a novel c.278G>A (p.G93D) variant with reduced functional activity. Echwald, S.M., Andersen, K.L., Sørensen, T.I., Larsen, L.H., Andersen, T., Tonooka, N., Tomura, H., Takeda, J., Pedersen, O. Hum. Mutat. (2004) [Pubmed]
  29. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Matthews, R.J., Bowne, D.B., Flores, E., Thomas, M.L. Mol. Cell. Biol. (1992) [Pubmed]
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