Human Molecular Genetics, 1999, Vol. 8, No. 9 1647-1655
© 1999 Oxford University Press
Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin
Institute of Medical Genetics and 1Department of Histopathology, University of Wales College of Medicine, Cardiff CF4 4XN, UK
We detected an interaction of the N-terminus of huntingtin (htt171) with the C-terminal region of the nuclear receptor co-repressor (N-CoR) using the yeast two-hybrid system. This interaction was repeat length dependent and specific to htt171; the co-repressor did not interact with the repeat carrying a section of atrophin 1 nor with the androgen receptor or polyglutamine alone. The interaction was confirmed using His-tagged Escherichia coli-expressed C-terminal human and rat co-repressor protein which pulled full-length huntingtin out of homogenized rat brain and in pull-down assays. The N-CoR represses transcription from sequence-specific ligand-activated receptors such as the retinoid X–thyroid hormone receptor dimers and other nuclear receptors including Mad–Max receptor dimers. The mechanism of this repression appears to be through the formation of a complex of repressor proteins including the N-CoR, mSin3 and histone deacetylases. We have used N-CoR and mSin3A antibodies in immunohistochemical studies and find that in Huntington’s disease (HD) cortex and caudate, the cellular localization of these proteins is exclusively cytoplasmic whilst in control brain they are localized in the nucleus as well as the cytoplasm; mSin3A immunoreactivity also occurred in a subset of huntingtin positive intranuclear inclusions. The relocalization of repressor proteins in HD brain may alter transcription and be involved in the pathology of the disease.
+ Present address: Zeneca Pharmaceuticals, Alderley Park, Cheshire SK10 4TG, UK
§ To whom correspondence should be addressed. Tel: +44 1222 745175; Fax: +44 1222 747603; Email: jones l1{at}cf.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M Futter, H Diekmann, E Schoenmakers, O Sadiq, K Chatterjee, and D C Rubinsztein Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors J. Med. Genet., July 1, 2009; 46(7): 438 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Runne, E. Regulier, A. Kuhn, D. Zala, O. Gokce, V. Perrin, B. Sick, P. Aebischer, N. Deglon, and R. Luthi-Carter Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry J. Neurosci., September 24, 2008; 28(39): 9723 - 9731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kuhn, D. R. Goldstein, A. Hodges, A. D. Strand, T. Sengstag, C. Kooperberg, K. Becanovic, M. A. Pouladi, K. Sathasivam, J.-H. J. Cha, et al. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage Hum. Mol. Genet., August 1, 2007; 16(15): 1845 - 1861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. O. Evert, J. Araujo, A. M. Vieira-Saecker, R. A. I. de Vos, S. Harendza, T. Klockgether, and U. Wullner Ataxin-3 Represses Transcription via Chromatin Binding, Interaction with Histone Deacetylase 3, and Histone Deacetylation. J. Neurosci., November 1, 2006; 26(44): 11474 - 11486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Bates, M. Victor, A. K. Jones, Y. Shi, and A. C. Hart Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J. Neurosci., March 8, 2006; 26(10): 2830 - 2838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kumar, A. E. Gururaj, R. K. Vadlamudi, and S. K. Rayala The Clinical Relevance of Steroid Hormone Receptor Corepressors Clin. Cancer Res., April 15, 2005; 11(8): 2822 - 2831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Lievens, T. Rival, M. Iche, H. Chneiweiss, and S. Birman Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila Hum. Mol. Genet., March 1, 2005; 14(5): 713 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Everett and N. W. Wood Trinucleotide repeats and neurodegenerative disease Brain, November 1, 2004; 127(11): 2385 - 2405. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schilling, A. V. Savonenko, A. Klevytska, J. L. Morton, S. M. Tucker, M. Poirier, A. Gale, N. Chan, V. Gonzales, H. H. Slunt, et al. Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice Hum. Mol. Genet., August 1, 2004; 13(15): 1599 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Tsai, H.-Y. Kao, A. Mitzutani, E. Banayo, H. Rajan, M. McKeown, and R. M. Evans Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors PNAS, March 23, 2004; 101(12): 4047 - 4052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ishihara, N. Yamagishi, Y. Saito, H. Adachi, Y. Kobayashi, G. Sobue, K. Ohtsuka, and T. Hatayama Hsp105{alpha} Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity J. Biol. Chem., June 27, 2003; 278(27): 25143 - 25150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Nucifora Jr., L. M. Ellerby, C. L. Wellington, J. D. Wood, W. J. Herring, A. Sawa, M. R. Hayden, V. L. Dawson, T. M. Dawson, and C. A. Ross Nuclear Localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity J. Biol. Chem., April 4, 2003; 278(15): 13047 - 13055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okuda, H. Hattori, S. Takeuchi, J. Shimizu, H. Ueda, J. J. Palvimo, I. Kanazawa, H. Kawano, M. Nakagawa, and H. Okazawa PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype Hum. Mol. Genet., April 1, 2003; 12(7): 711 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gines, I. S. Seong, E. Fossale, E. Ivanova, F. Trettel, J. F. Gusella, V. C. Wheeler, F. Persichetti, and M. E. MacDonald Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice Hum. Mol. Genet., March 1, 2003; 12(5): 497 - 508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Li, T. Macfarlan, R. N. Pittman, and D. Chakravarti Ataxin-3 Is a Histone-binding Protein with Two Independent Transcriptional Corepressor Activities J. Biol. Chem., November 15, 2002; 277(47): 45004 - 45012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Singaraja, S. Hadano, M. Metzler, S. Givan, C. L. Wellington, S. Warby, A. Yanai, C.-A. Gutekunst, B. R. Leavitt, H. Yi, et al. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis Hum. Mol. Genet., November 1, 2002; 11(23): 2815 - 2828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kazemi-Esfarjani and S. Benzer Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1 Hum. Mol. Genet., October 2, 2002; 11(21): 2657 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Fossale, V. C. Wheeler, V. Vrbanac, L.-A. Lebel, A. Teed, J. S. Mysore, J. F. Gusella, M. E. MacDonald, and F. Persichetti Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice Hum. Mol. Genet., September 15, 2002; 11(19): 2233 - 2241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kita, J. Carmichael, J. Swartz, S. Muro, A. Wyttenbach, K. Matsubara, D. C. Rubinsztein, and K. Kato Modulation of polyglutamine-induced cell death by genes identified by expression profiling Hum. Mol. Genet., September 15, 2002; 11(19): 2279 - 2287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Bennett, K. E. Huey-Tubman, A. B. Herr, A. P. West Jr., S. A. Ross, and P. J. Bjorkman Inaugural Article: A linear lattice model for polyglutamine in CAG-expansion diseases PNAS, September 3, 2002; 99(18): 11634 - 11639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Luthi-Carter, S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain Hum. Mol. Genet., August 15, 2002; 11(17): 1911 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Luthi-Carter, A. D. Strand, S. A. Hanson, C. Kooperberg, G. Schilling, A. R. La Spada, D. E. Merry, A. B. Young, C. A. Ross, D. R. Borchelt, et al. Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects Hum. Mol. Genet., August 15, 2002; 11(17): 1927 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Y.W. Chan, R. Luthi-Carter, A. Strand, S. M. Solano, S. A. Hanson, M. M. DeJohn, C. Kooperberg, K. O. Chase, M. DiFiglia, A. B. Young, et al. Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease Hum. Mol. Genet., August 15, 2002; 11(17): 1939 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Lieberman, G. Harmison, A. D. Strand, J. M. Olson, and K. H. Fischbeck Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor Hum. Mol. Genet., August 15, 2002; 11(17): 1967 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Takahashi, H. Fujigasaki, C. Zander, K. H. El Hachimi, G. Stevanin, A. Durr, A.-S. Lebre, G. Yvert, Y. Trottier, H. d. The, et al. Two populations of neuronal intranuclear inclusions in SCA7 differ in size and promyelocytic leukaemia protein content Brain, July 1, 2002; 125(7): 1534 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Dunah, H. Jeong, A. Griffin, Y.-M. Kim, D. G. Standaert, S. M. Hersch, M. M. Mouradian, A. B. Young, N. Tanese, and D. Krainc Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease Science, June 21, 2002; 296(5576): 2238 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-X. Yu, S.-H. Li, H.-P. Nguyen, and X.-J. Li Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice Hum. Mol. Genet., April 15, 2002; 11(8): 905 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Li, A. L. Cheng, H. Zhou, S. Lam, M. Rao, H. Li, and X.-J. Li Interaction of Huntington Disease Protein with Transcriptional Activator Sp1 Mol. Cell. Biol., March 1, 2002; 22(5): 1277 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. B. Kegel, A. R. Meloni, Y. Yi, Y. J. Kim, E. Doyle, B. G. Cuiffo, E. Sapp, Y. Wang, Z.-H. Qin, J. D. Chen, et al. Huntingtin Is Present in the Nucleus, Interacts with the Transcriptional Corepressor C-terminal Binding Protein, and Represses Transcription J. Biol. Chem., February 22, 2002; 277(9): 7466 - 7476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Jepsen and M. G. Rosenfeld Biological roles and mechanistic actions of co-repressor complexes J. Cell Sci., February 15, 2002; 115(4): 689 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Yvert, K. S. Lindenberg, D. Devys, D. Helmlinger, G. B. Landwehrmeyer, and J.-L. Mandel SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types Hum. Mol. Genet., August 1, 2001; 10(16): 1679 - 1692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, S.-Y. Jeong, T. Uchihara, M. Anno, K. Nagashima, T. Nagashima, S.-i. Ikeda, S. Tsuji, and I. Kanazawa SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein Hum. Mol. Genet., July 1, 2001; 10(14): 1441 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Jana, E. A. Zemskov, G.-h. Wang, and N. Nukina Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release Hum. Mol. Genet., May 1, 2001; 10(10): 1049 - 1059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Holbert, I. Denghien, T. Kiechle, A. Rosenblatt, C. Wellington, M. R. Hayden, R. L. Margolis, C. A. Ross, J. Dausset, R. J. Ferrante, et al. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis PNAS, January 24, 2001; (2001) 41566798. [Abstract] [Full Text]
|
|
|
|
|
|
P. Hilditch-Maguire, F. Trettel, L. A. Passani, A. Auerbach, F. Persichetti, and M. E. MacDonald Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles Hum. Mol. Genet., November 1, 2000; 9(19): 2789 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Trettel, D. Rigamonti, P. Hilditch-Maguire, V. C. Wheeler, A. H. Sharp, F. Persichetti, E. Cattaneo, and M. E. MacDonald Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells Hum. Mol. Genet., November 1, 2000; 9(19): 2799 - 2809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Wood, F. C. Nucifora Jr., K. Duan, C. Zhang, J. Wang, Y. Kim, G. Schilling, N. Sacchi, J. M. Liu, and C. A. Ross Atrophin-1, the Dentato-Rubral and Pallido-Luysian Atrophy Gene Product, Interacts with Eto/Mtg8 in the Nuclear Matrix and Represses Transcription J. Cell Biol., September 4, 2000; 150(5): 939 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Passani, M. T. Bedford, P. W. Faber, K. M. McGinnis, A. H. Sharp, J. F. Gusella, J.-P. Vonsattel, and M. E. MacDonald Huntingtin's WW domain partners in Huntington's disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington's disease pathogenesis Hum. Mol. Genet., September 1, 2000; 9(14): 2175 - 2182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. McCampbell, J. P. Taylor, A. A. Taye, J. Robitschek, M. Li, J. Walcott, D. Merry, Y. Chai, H. Paulson, G. Sobue, et al. CREB-binding protein sequestration by expanded polyglutamine Hum. Mol. Genet., September 1, 2000; 9(14): 2197 - 2202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Luthi-Carter, A. Strand, N. L. Peters, S. M. Solano, Z. R. Hollingsworth, A. S. Menon, A. S. Frey, B. S. Spektor, E. B. Penney, G. Schilling, et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease Hum. Mol. Genet., May 22, 2000; 9(9): 1259 - 1271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Cummings and H. Y. Zoghbi Fourteen and counting: unraveling trinucleotide repeat diseases Hum. Mol. Genet., April 1, 2000; 9(6): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Metzler, C. D. Helgason, I. Dragatsis, T. Zhang, L. Gan, N. Pineault, S. O. Zeitlin, R. K. Humphries, and M. R. Hayden Huntingtin is required for normal hematopoiesis Hum. Mol. Genet., February 12, 2000; 9(3): 387 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Peters and C. A. Ross Isolation of a 40-kDa Huntingtin-associated Protein J. Biol. Chem., January 26, 2001; 276(5): 3188 - 3194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Hackam, A. S. Yassa, R. Singaraja, M. Metzler, C.-A. Gutekunst, L. Gan, S. Warby, C. L. Wellington, J. Vaillancourt, N. Chen, et al. Huntingtin Interacting Protein 1 Induces Apoptosis via a Novel Caspase-dependent Death Effector Domain J. Biol. Chem., December 22, 2000; 275(52): 41299 - 41308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khoshnan, J. Ko, and P. H. Patterson Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity PNAS, January 22, 2002; 99(2): 1002 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Holbert, I. Denghien, T. Kiechle, A. Rosenblatt, C. Wellington, M. R. Hayden, R. L. Margolis, C. A. Ross, J. Dausset, R. J. Ferrante, et al. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis PNAS, February 13, 2001; 98(4): 1811 - 1816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Hughes, R. S. Lo, C. Davis, A. D. Strand, C. L. Neal, J. M. Olson, and S. Fields Altered transcription in yeast expressing expanded polyglutamine PNAS, November 6, 2001; 98(23): 13201 - 13206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. McCampbell, A. A. Taye, L. Whitty, E. Penney, J. S. Steffan, and K. H. Fischbeck Histone deacetylase inhibitors reduce polyglutamine toxicity PNAS, December 18, 2001; 98(26): 15179 - 15184. [Abstract] [Full Text] [PDF]
|
|