This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seol, W. Articles by Moore, D. D. Search for Related Content PubMed PubMed Citation Articles by Seol, W. Articles by Moore, D. D.

 Previous Article  |  Next Article 

Mol. Cell. Biol., Dec 1997, 7126-7131, Vol 17, No. 12
Copyright © 1997, American Society for Microbiology

Novel receptor interaction and repression domains in the orphan receptor SHP

W Seol, M Chung and DD Moore
Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA.

SHP (short heterodimer partner) is a novel orphan receptor that lacks a conventional DNA binding domain and interacts with other members of the nuclear hormone receptor superfamily. We have characterized the SHP sequences required for interaction with other superfamily members, and have defined an SHP repressor domain. In the mammalian two-hybrid system, a fusion of full-length SHP to the GAL4 DNA binding domain shows 9-cis-retinoic acid-dependent interaction with a VP16-retinoid X receptor alpha (RXR alpha) fusion. By deletion analysis, sequences required for this RXR interaction map to the central portion of SHP (amino acids 92 to 148). The same region is required for interaction with RXR in vitro and in the yeast two-hybrid system, and results from the yeast system suggest that the same SHP sequences are required for interaction with other members of the nuclear hormone receptor superfamily such as thyroid hormone receptor and retinoic acid receptor. In mammalian cells, a GAL4-SHP fusion protein shows about 10- fold-decreased transcriptional activation relative to GAL4 alone, and fusion of SHP to the C terminus of a GAL4-VP16 fusion to generate a triple chimera also results in a strong decrease in transactivation activity. Sequences required for this repressor function were mapped to the C terminus of SHP. This region is distinct from that required for corepressor interaction by other members of the nuclear hormone receptor superfamily, and SHP did not interact with N-CoR in either the yeast or mammalian two-hybrid system. Together, these results identify novel receptor interaction and repressor domains in SHP and suggest two distinct mechanisms for inhibition of receptor signaling pathways by SHP.

This article has been cited by other articles:

• Seo, H.-Y., Kim, Y. D., Lee, K.-M., Min, A.-K., Kim, M.-K., Kim, H.-S., Won, K.-C., Park, J.-Y., Lee, K.-U., Choi, H.-S., Park, K.-G., Lee, I.-K. (2008). Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner. Endocrinology 149: 3832-3841 [Abstract] [Full Text]  
• Oropeza, C. E., Li, L., McLachlan, A. (2008). Differential Inhibition of Nuclear Hormone Receptor-Dependent Hepatitis B Virus Replication by the Small Heterodimer Partner. J. Virol. 82: 3814-3821 [Abstract] [Full Text]  
• Park, K.-G., Lee, K.-M., Seo, H.-Y., Suh, J.-H., Kim, H.-S., Wang, L., Won, K.-C., Lee, H.-W., Park, J.-Y., Lee, K.-U., Kim, J.-G., Kim, B.-W., Choi, H.-S., Lee, I.-K. (2007). Glucotoxicity in the INS-1 Rat Insulinoma Cell Line Is Mediated by the Orphan Nuclear Receptor Small Heterodimer Partner. Diabetes 56: 431-437 [Abstract] [Full Text]  
• Farhana, L., Dawson, M. I., Leid, M., Wang, L., Moore, D. D., Liu, G., Xia, Z., Fontana, J. A. (2007). Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor. Cancer Res. 67: 318-325 [Abstract] [Full Text]  
• Folkertsma, S., van Noort, P. I., de Heer, A., Carati, P., Brandt, R., Visser, A., Vriend, G., de Vlieg, J. (2007). The Use of in Vitro Peptide Binding Profiles and in Silico Ligand-Receptor Interaction Profiles to Describe Ligand-Induced Conformations of the Retinoid X Receptor {alpha} Ligand-Binding Domain. Mol. Endocrinol. 21: 30-48 [Abstract] [Full Text]  
• Suh, J. H., Huang, J., Park, Y.-Y., Seong, H.-A, Kim, D., Shong, M., Ha, H., Lee, I.-K., Lee, K., Wang, L., Choi, H.-S. (2006). Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation. J. Biol. Chem. 281: 39169-39178 [Abstract] [Full Text]  
• Benoit, G., Cooney, A., Giguere, V., Ingraham, H., Lazar, M., Muscat, G., Perlmann, T., Renaud, J.-P., Schwabe, J., Sladek, F., Tsai, M.-J., Laudet, V. (2006). International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 58: 798-836 [Abstract] [Full Text]  
• Wang, L., Huang, J., Saha, P., Kulkarni, R. N., Hu, M., Kim, Y., Park, K., Chan, L., Rajan, A. S., Lee, I., Moore, D. D. (2006). Orphan Receptor Small Heterodimer Partner Is an Important Mediator of Glucose Homeostasis. Mol. Endocrinol. 20: 2671-2681 [Abstract] [Full Text]  
• Zhao, Y., Yang, Z., Phelan, J. K., Wheeler, D. A., Lin, S., McCabe, E. R. B. (2006). Zebrafish dax1 Is Required for Development of the Interrenal Organ, the Adrenal Cortex Equivalent. Mol. Endocrinol. 20: 2630-2640 [Abstract] [Full Text]  
• Iyer, A. K., Zhang, Y.-H., McCabe, E. R. B. (2006). Dosage-Sensitive Sex Reversal Adrenal Hypoplasia Congenita Critical Region on the X Chromosome, Gene 1 (DAX1) (NR0B1) and Small Heterodimer Partner (SHP) (NR0B2) Form Homodimers Individually, as Well as DAX1-SHP Heterodimers. Mol. Endocrinol. 20: 2326-2342 [Abstract] [Full Text]  
• Gu, P., Morgan, D. H., Sattar, M., Xu, X., Wagner, R., Raviscioni, M., Lichtarge, O., Cooney, A. J. (2005). Evolutionary Trace-based Peptides Identify a Novel Asymmetric Interaction That Mediates Oligomerization in Nuclear Receptors. J. Biol. Chem. 280: 31818-31829 [Abstract] [Full Text]  
• Kumar, R., Gururaj, A. E., Vadlamudi, R. K., Rayala, S. K. (2005). The Clinical Relevance of Steroid Hormone Receptor Corepressors. Clin. Cancer Res. 11: 2822-2831 [Abstract] [Full Text]  
• Moore, J. M. R., Guy, R. K. (2005). Coregulator Interactions with the Thyroid Hormone Receptor. Mol. Cell. Proteomics 4: 475-482 [Abstract] [Full Text]  
• Kim, J.-Y., Kim, H.-J., Kim, K. T., Park, Y.-Y., Seong, H.-A, Park, K. C., Lee, I.-K., Ha, H., Shong, M., Park, S. C., Choi, H.-S. (2004). Orphan Nuclear Receptor Small Heterodimer Partner Represses Hepatocyte Nuclear Factor 3/Foxa Transactivation via Inhibition of Its DNA Binding. Mol. Endocrinol. 18: 2880-2894 [Abstract] [Full Text]  
• Boulias, K., Talianidis, I. (2004). Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression. Nucleic Acids Res 32: 6096-6103 [Abstract] [Full Text]  
• Choi, Y. H., Park, M. J., Kim, K. W., Lee, H. C., Choi, Y. H., Cheong, J. (2004). The orphan nuclear receptor SHP is involved in monocytic differentiation, and its expression is increased by c-Jun. J. Leukoc. Biol. 76: 1082-1088 [Abstract] [Full Text]  
• Suh, Y-H, Kim, S-Y, Lee, H-Y, Jang, B C, Bae, J H, Sohn, J-N, Bae, J-H, Suh, S-I, Park, J-W, Lee, K-U, Song, D-K (2004). Overexpression of short heterodimer partner recovers impaired glucose-stimulated insulin secretion of pancreatic {beta}-cells overexpressing UCP2. J Endocrinol 183: 133-144 [Abstract] [Full Text]  
• Kemper, J. K., 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: 7707-7719 [Abstract] [Full Text]  
• 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. (2004). Differential Regulation of Human and Mouse Orphan Nuclear Receptor Small Heterodimer Partner Promoter by Sterol Regulatory Element Binding Protein-1. J. Biol. Chem. 279: 28122-28131 [Abstract] [Full Text]  
• Kim, J.-Y., Chu, K., Kim, H.-J., Seong, H.-A, Park, K.-C., Sanyal, S., Takeda, J., Ha, H., Shong, M., Tsai, M.-J., Choi, H.-S. (2004). Orphan Nuclear Receptor Small Heterodimer Partner, a Novel Corepressor for a Basic Helix-Loop-Helix Transcription Factor BETA2/NeuroD. Mol. Endocrinol. 18: 776-790 [Abstract] [Full Text]  
• Shimamoto, Y., Ishida, J., Yamagata, K., Saito, T., Kato, H., Matsuoka, T., Hirota, K., Daitoku, H., Nangaku, M., Yamagata, K., Fujii, H., Takeda, J., Fukamizu, A. (2004). Inhibitory Effect of the Small Heterodimer Partner on Hepatocyte Nuclear Factor-4 Mediates Bile Acid-induced Repression of the Human Angiotensinogen Gene. J. Biol. Chem. 279: 7770-7776 [Abstract] [Full Text]  
• Kim, H.-J., Kim, J.-Y., Park, Y.-Y., Choi, H.-S. (2003). Synergistic activation of the human orphan nuclear receptor SHP gene promoter by basic helix-loop-helix protein E2A and orphan nuclear receptor SF-1. Nucleic Acids Res 31: 6860-6872 [Abstract] [Full Text]  
• Lin, V. Y., Resnick, E. M., Shupnik, M. A. (2003). Truncated Estrogen Receptor Product-1 Stimulates Estrogen Receptor {alpha} Transcriptional Activity by Titration of Repressor Proteins. J. Biol. Chem. 278: 38125-38131 [Abstract] [Full Text]  
• Fayard, E., Schoonjans, K., Annicotte, J.-S., Auwerx, J. (2003). Liver Receptor Homolog 1 Controls the Expression of Carboxyl Ester Lipase. J. Biol. Chem. 278: 35725-35731 [Abstract] [Full Text]  
• Ourlin, J. C., Lasserre, F., Pineau, T., Fabre, J. M., Sa-Cunha, A., Maurel, P., Vilarem, M.-J., Pascussi, J. M. (2003). The Small Heterodimer Partner Interacts with the Pregnane X Receptor and Represses Its Transcriptional Activity. Mol. Endocrinol. 17: 1693-1703 [Abstract] [Full Text]  
• Wiederschain, D., Kawai, H., Gu, J., Shilatifard, A., Yuan, Z.-M. (2003). Molecular Basis of p53 Functional Inactivation by the Leukemic Protein MLL-ELL. Mol. Cell. Biol. 23: 4230-4246 [Abstract] [Full Text]  
• Hung, C.-C. C., Farooqi, I. S., Ong, K., Luan, J.'a., Keogh, J. M., Pembrey, M., Yeo, G. S.H., Dunger, D., Wareham, N. J., O' Rahilly, S. (2003). Contribution of Variants in the Small Heterodimer Partner Gene to Birthweight, Adiposity, and Insulin Levels: Mutational Analysis and Association Studies in Multiple Populations. Diabetes 52: 1288-1291 [Abstract] [Full Text]  
• Brendel, C., Schoonjans, K., Botrugno, O. A., Treuter, E., Auwerx, J. (2002). The Small Heterodimer Partner Interacts with the Liver X Receptor {alpha} and Represses Its Transcriptional Activity. Mol. Endocrinol. 16: 2065-2076 [Abstract] [Full Text]  
• Li, D., Zimmerman, T. L., Thevananther, S., Lee, H.-Y., Kurie, J. M., Karpen, S. J. (2002). Interleukin-1beta -mediated Suppression of RXR:RAR Transactivation of the Ntcp Promoter Is JNK-dependent. J. Biol. Chem. 277: 31416-31422 [Abstract] [Full Text]  
• Chiang, J. Y. L. (2002). Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors. Endocr. Rev. 23: 443-463 [Abstract] [Full Text]  
• Seo, Y.-W., Sanyal, S., Kim, H.-J., Won, D. H., An, J.-Y., Amano, T., Zavacki, A. M., Kwon, H.-B., Shi, Y.-B., Kim, W.-S., Kang, H., Moore, D. D., Choi, H.-S. (2002). FOR, a Novel Orphan Nuclear Receptor Related to Farnesoid X Receptor. J. Biol. Chem. 277: 17836-17844 [Abstract] [Full Text]  
• Klinge, C. M., Jernigan, S. C., Risinger, K. E. (2002). The Agonist Activity of Tamoxifen Is Inhibited by the Short Heterodimer Partner Orphan Nuclear Receptor in Human Endometrial Cancer Cells. Endocrinology 143: 853-867 [Abstract] [Full Text]  
• del Castillo-Olivares, A., Gil, G. (2002). Differential Effects of Sterol Regulatory Binding Proteins 1 and 2 on Sterol 12alpha -Hydroxylase. SREBP-2 SUPPRESSES THE STEROL 12alpha -HYDROXYLASE PROMOTER. J. Biol. Chem. 277: 6750-6757 [Abstract] [Full Text]  
• Sinal, C. J., Yoon, M., Gonzalez, F. J. (2001). Antagonism of the Actions of Peroxisome Proliferator-activated Receptor-alpha by Bile Acids. J. Biol. Chem. 276: 47154-47162 [Abstract] [Full Text]  
• del Castillo-Olivares, A., Gil, G. (2001). Suppression of sterol 12{alpha}-hydroxylase transcription by the short heterodimer partner: insights into the repression mechanism. Nucleic Acids Res 29: 4035-4042 [Abstract] [Full Text]  
• Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., Gustafsson, J.-A. (2001). Mechanisms of Estrogen Action. Physiol. Rev. 81: 1535-1565 [Abstract] [Full Text]  
• Aranda, A., Pascual, A. (2001). Nuclear Hormone Receptors and Gene Expression. Physiol. Rev. 81: 1269-1304 [Abstract] [Full Text]  
• 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. (2000). Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc. Natl. Acad. Sci. USA 10.1073/pnas.021544398v1 [Abstract] [Full Text]  
• Resnick, E. M., Schreihofer, D. A., Periasamy, A., Shupnik, M. A. (2000). Truncated Estrogen Receptor Product-1 Suppresses Estrogen Receptor Transactivation by Dimerization with Estrogen Receptors alpha and beta. J. Biol. Chem. 275: 7158-7166 [Abstract] [Full Text]  
• Johansson, L., Båvner, A., Thomsen, J. S., Färnegårdh, M., Gustafsson, J.-A., Treuter, E. (2000). The Orphan Nuclear Receptor SHP Utilizes Conserved LXXLL-Related Motifs for Interactions with Ligand-Activated Estrogen Receptors. Mol. Cell. Biol. 20: 1124-1133 [Abstract] [Full Text]  
• Lee, Y.-K., Dell, H., Dowhan, D. H., Hadzopoulou-Cladaras, M., Moore, D. D. (2000). The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression. Mol. Cell. Biol. 20: 187-195 [Abstract] [Full Text]  
• Giguère, V. (1999). Orphan Nuclear Receptors: From Gene to Function. Endocr. Rev. 20: 689-725 [Abstract] [Full Text]  
• Lee, Y.-K., Parker, K. L., Choi, H.-S., Moore, D. D. (1999). Activation of the Promoter of the Orphan Receptor SHP by Orphan Receptors That Bind DNA as Monomers. J. Biol. Chem. 274: 20869-20873 [Abstract] [Full Text]  
• Greschik, H., Wurtz, J.-M., Hublitz, P., Kohler, F., Moras, D., Schule, R. (1999). Characterization of the DNA-Binding and Dimerization Properties of the Nuclear Orphan Receptor Germ Cell Nuclear Factor. Mol. Cell. Biol. 19: 690-703 [Abstract] [Full Text]  
• Johansson, L., Thomsen, J. S., Damdimopoulos, A. E., Spyrou, G., Gustafsson, J.-A., Treuter, E. (1999). The Orphan Nuclear Receptor SHP Inhibits Agonist-dependent Transcriptional Activity of Estrogen Receptors ERalpha and ERbeta. J. Biol. Chem. 274: 345-353 [Abstract] [Full Text]  
• Seol, W., Hanstein, B., Brown, M., Moore, D. D. (1998). Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner). Mol. Endocrinol. 12: 1551-1557 [Abstract] [Full Text]  
• Kim, H.-J., Lee, S.-K., Na, S.-Y., Choi, H.-S., Lee, J. W. (1998). Molecular Cloning of xSRC-3, a Novel Transcription Coactivator from Xenopus, That Is Related to AIB1, p/CIP, and TIF2. Mol. Endocrinol. 12: 1038-1047 [Abstract] [Full Text]  
• 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. (2001). 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. J. Biol. Chem. 276: 33736-33740 [Abstract] [Full Text]  
• 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. (2002). Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor gamma Transactivation. J. Biol. Chem. 277: 1586-1592 [Abstract] [Full Text]  
• Lee, Y.-K., Moore, D. D. (2002). Dual Mechanisms for Repression of the Monomeric Orphan Receptor Liver Receptor Homologous Protein-1 by the Orphan Small Heterodimer Partner. J. Biol. Chem. 277: 2463-2467 [Abstract] [Full Text]  
• Sanyal, S., Kim, J.-Y., Kim, H.-J., Takeda, J., Lee, Y.-K., Moore, D. D., Choi, H.-S. (2002). Differential Regulation of the Orphan Nuclear Receptor Small Heterodimer Partner (SHP) Gene Promoter by Orphan Nuclear Receptor ERR Isoforms. J. Biol. Chem. 277: 1739-1748 [Abstract] [Full Text]  
• Lu, T. T., Repa, J. J., Mangelsdorf, D. J. (2001). Orphan Nuclear Receptors as eLiXiRs and FiXeRs of Sterol Metabolism. J. Biol. Chem. 276: 37735-37738 [Full Text]  
• 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. (2001). Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc. Natl. Acad. Sci. USA 98: 575-580 [Abstract] [Full Text]