Human Molecular Genetics, 2001, Vol. 10, No. 17 1829-1845
© 2001 Oxford University Press
Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington’s disease
Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK, 1Taisho Laboratory of Functional Genomics, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0101, Japan, 2Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Brendstrupgaardsvej, 8200 Aarhus N., Denmark and 3University Department of Clinical Neurosciences, Royal Free and University College Medical School, UCL, London NW3 2PF, and Institute of Neurology, Queen Square, London WC1N 3BG, UK
Huntington’s disease (HD) is one of 10 known diseases caused by a (CAG)n trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract. We have developed stable inducible neuronal (PC12) cell lines that express huntingtin exon 1 with varying CAG repeat lengths under doxycycline (dox) control. The expression of expanded repeats is associated with aggregate formation, caspase-dependent cell death and decreased neurite outgrowth. Post-mitotic cells expressing mutant alleles were more prone to cell death compared with identical cycling cells. To determine early metabolic changes induced by this mutation in cell models, we studied changes in gene expression after 18 h dox induction, using Affymetrix arrays, cDNA filters and adapter-tagged competitive PCR (ATAC-PCR). At this time point there were low rates of inclusion formation, no evidence of mitochondrial compromise and no excess cell death in the lines expressing expanded compared with wild-type repeats. The expression profiles suggest novel targets for the HD mutation and were compatible with impaired cAMP response element (CRE)-mediated transcription, which we confirmed using CRE-luciferase reporter assays. Reduced CRE-mediated transcription may contribute to the loss of neurite outgrowth and cell death in polyglutamine diseases, as these phenotypes were partially rescued by treating cells with cAMP or forskolin.
+ To whom correspondence should be addressed. Tel: +44 1223 762608; Fax: +44 1223 331206; Email: dcr1000@cus.cam.ac.uk The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Carnemolla, E. Fossale, E. Agostoni, S. Michelazzi, R. Calligaris, L. De Maso, G. Del Sal, M. E. MacDonald, and F. Persichetti Rrs1 Is Involved in Endoplasmic Reticulum Stress Response in Huntington Disease J. Biol. Chem., July 3, 2009; 284(27): 18167 - 18173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 O. Anichtchik, H. Diekmann, A. Fleming, A. Roach, P. Goldsmith, and D. C. Rubinsztein Loss of PINK1 Function Affects Development and Results in Neurodegeneration in Zebrafish J. Neurosci., August 13, 2008; 28(33): 8199 - 8207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Ravikumar, S. Imarisio, S. Sarkar, C. J. O'Kane, and D. C. Rubinsztein Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease J. Cell Sci., May 15, 2008; 121(10): 1649 - 1660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. King, S. Hands, F. Hafiz, N. Mizushima, A. M. Tolkovsky, and A. Wyttenbach Rapamycin Inhibits Polyglutamine Aggregation Independently of Autophagy by Reducing Protein Synthesis Mol. Pharmacol., April 1, 2008; 73(4): 1052 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stefani Generic Cell Dysfunction in Neurodegenerative Disorders: Role of Surfaces in Early Protein Misfolding, Aggregation, and Aggregate Cytotoxicity Neuroscientist, October 1, 2007; 13(5): 519 - 531. [Abstract] [PDF]
|
|
|
|
 |
|
 M.-C. Chiang, C.-G. Juo, H.-H. Chang, H.-M. Chen, E. C. Yi, and Y. Chern Systematic Uncovering of Multiple Pathways Underlying the Pathology of Huntington Disease by an Acid-cleavable Isotope-coded Affinity Tag Approach Mol. Cell. Proteomics, May 1, 2007; 6(5): 781 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Fukui and C. T. Moraes Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates Hum. Mol. Genet., April 1, 2007; 16(7): 783 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarkar, J. E. Davies, Z. Huang, A. Tunnacliffe, and D. C. Rubinsztein Trehalose, a Novel mTOR-independent Autophagy Enhancer, Accelerates the Clearance of Mutant Huntingtin and {alpha}-Synuclein J. Biol. Chem., February 23, 2007; 282(8): 5641 - 5652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N.T. Strehlow, J. Z. Li, and R. M. Myers Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space Hum. Mol. Genet., February 15, 2007; 16(4): 391 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tagawa, S. Marubuchi, M.-L. Qi, Y. Enokido, T. Tamura, R. Inagaki, M. Murata, I. Kanazawa, E. E. Wanker, and H. Okazawa The Induction Levels of Heat Shock Protein 70 Differentiate the Vulnerabilities to Mutant Huntingtin among Neuronal Subtypes J. Neurosci., January 24, 2007; 27(4): 868 - 880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Smith, H. Chung, S. Rundquist, M. L.C. Maat-Schieman, L. Colgan, E. Englund, Y.-J. Liu, R. A.C. Roos, R. L.M. Faull, P. Brundin, et al. Cholinergic neuronal defect without cell loss in Huntington's disease Hum. Mol. Genet., November 1, 2006; 15(21): 3119 - 3131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J E Davies and D C Rubinsztein Polyalanine and polyserine frameshift products in Huntington's disease J. Med. Genet., November 1, 2006; 43(11): 893 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rong, J. R. McGuire, Z.-H. Fang, G. Sheng, J.-Y. Shin, S.-H. Li, and X.-J. Li Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth. J. Neurosci., May 31, 2006; 26(22): 6019 - 6030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Berger, J. E. Davies, S. Luo, M. Y. Pasco, I. Majoul, C. J. O'Kane, and D. C. Rubinsztein Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion Hum. Mol. Genet., February 1, 2006; 15(3): 453 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Apostol, K. Illes, J. Pallos, L. Bodai, J. Wu, A. Strand, E. S. Schweitzer, J. M. Olson, A. Kazantsev, J. L. Marsh, et al. Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity Hum. Mol. Genet., January 15, 2006; 15(2): 273 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Davies, S. Sarkar, and D. C. Rubinsztein Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy Hum. Mol. Genet., January 1, 2006; 15(1): 23 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lee, C.-H. Kim, D. K. Simon, L. R. Aminova, A. Y. Andreyev, Y. E. Kushnareva, A. N. Murphy, B. E. Lonze, K.-S. Kim, D. D. Ginty, et al. Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival J. Biol. Chem., December 9, 2005; 280(49): 40398 - 40401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Katsuno, C. Sang, H. Adachi, M. Minamiyama, M. Waza, F. Tanaka, M. Doyu, and G. Sobue Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease PNAS, November 15, 2005; 102(46): 16801 - 16806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Matsumoto, A. Stojanovic, C. I. Holmberg, S. Kim, and R. I. Morimoto Structural properties and neuronal toxicity of amyotrophic lateral sclerosis-associated Cu/Zn superoxide dismutase 1 aggregates J. Cell Biol., October 10, 2005; 171(1): 75 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarkar, R. A. Floto, Z. Berger, S. Imarisio, A. Cordenier, M. Pasco, L. J. Cook, and D. C. Rubinsztein Lithium induces autophagy by inhibiting inositol monophosphatase J. Cell Biol., September 26, 2005; 170(7): 1101 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Iijima-Ando, P. Wu, E. A. Drier, K. Iijima, and J. C. P. Yin cAMP-response element-binding protein and heat-shock protein 70 additively suppress polyglutamine-mediated toxicity in Drosophila PNAS, July 19, 2005; 102(29): 10261 - 10266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Chiang, Y.-C. Lee, C.-L. Huang, and Y. Chern cAMP-response Element-binding Protein Contributes to Suppression of the A2A Adenosine Receptor Promoter by Mutant Huntingtin with Expanded Polyglutamine Residues J. Biol. Chem., April 8, 2005; 280(14): 14331 - 14340. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Trushina, R. B. Dyer, J. D. Badger II, D. Ure, L. Eide, D. D. Tran, B. T. Vrieze, V. Legendre-Guillemin, P. S. McPherson, B. S. Mandavilli, et al. Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro Mol. Cell. Biol., September 15, 2004; 24(18): 8195 - 8209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Colton, Q. Xu, J. R. Burke, S. Y. Bae, J. K. Wakefield, A. Nair, W. J. Strittmatter, and M. P. Vitek Disrupted Spermine Homeostasis: A Novel Mechanism in Polyglutamine-Mediated Aggregation and Cell Death J. Neurosci., August 11, 2004; 24(32): 7118 - 7127. [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]
|
|
|
|
|
|
M. Minamiyama, M. Katsuno, H. Adachi, M. Waza, C. Sang, Y. Kobayashi, F. Tanaka, M. Doyu, A. Inukai, and G. Sobue Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy Hum. Mol. Genet., June 1, 2004; 13(11): 1183 - 1192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Sugars, R. Brown, L. J. Cook, J. Swartz, and D. C. Rubinsztein Decreased cAMP Response Element-mediated Transcription: AN EARLY EVENT IN EXON 1 AND FULL-LENGTH CELL MODELS OF HUNTINGTON'S DISEASE THAT CONTRIBUTES TO POLYGLUTAMINE PATHOGENESIS J. Biol. Chem., February 6, 2004; 279(6): 4988 - 4999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Obrietan and K. R. Hoyt CRE-Mediated Transcription Is Increased in Huntington's Disease Transgenic Mice J. Neurosci., January 28, 2004; 24(4): 791 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y P Bao, S Sarkar, E Uyama, and D C Rubinsztein Congo red, doxycycline, and HSP70 overexpression reduce aggregate formation and cell death in cell models of oculopharyngeal muscular dystrophy J. Med. Genet., January 1, 2004; 41(1): 47 - 51. [Full Text] [PDF]
|
|
|
|
|
|
A. Michalik and C. Van Broeckhoven Pathogenesis of polyglutamine disorders: aggregation revisited Hum. Mol. Genet., October 15, 2003; 12(90002): R173 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Trushina, M. P. Heldebrant, C. M. Perez-Terzic, R. Bortolon, I. V. Kovtun, J. D. Badger II, A. Terzic, A. Estevez, A. J. Windebank, R. B. Dyer, et al. Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease PNAS, October 14, 2003; 100(21): 12171 - 12176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Giuliano, T. de Cristofaro, A. Affaitati, G. M. Pizzulo, A. Feliciello, C. Criscuolo, G. De Michele, A. Filla, E. V. Avvedimento, and S. Varrone DNA damage induced by polyglutamine-expanded proteins Hum. Mol. Genet., September 15, 2003; 12(18): 2301 - 2309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Edwardson, C.-T. Wang, B. Gong, A. Wyttenbach, J. Bai, M. B. Jackson, E. R. Chapman, and A. J. Morton Expression of Mutant Huntingtin Blocks Exocytosis in PC12 Cells by Depletion of Complexin II J. Biol. Chem., August 15, 2003; 278(33): 30849 - 30853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Apostol, A. Kazantsev, S. Raffioni, K. Illes, J. Pallos, L. Bodai, N. Slepko, J. E. Bear, F. B. Gertler, S. Hersch, et al. A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila PNAS, May 13, 2003; 100(10): 5950 - 5955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ravikumar, A. Stewart, H. Kita, K. Kato, R. Duden, and D. C. Rubinsztein Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy Hum. Mol. Genet., May 1, 2003; 12(9): 985 - 994. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 E. Cattaneo Dysfunction of Wild-Type Huntingtin in Huntington disease Physiology, February 1, 2003; 18(1): 34 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jiang, F. C. Nucifora Jr, C. A. Ross, and D. B. DeFranco Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein Hum. Mol. Genet., January 1, 2003; 12(1): 1 - 12. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Carmichael, K. L. Sugars, Y. P. Bao, and D. C. Rubinsztein Glycogen Synthase Kinase-3beta Inhibitors Prevent Cellular Polyglutamine Toxicity Caused by the Huntington's Disease Mutation J. Biol. Chem., September 6, 2002; 277(37): 33791 - 33798. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Sipione, D. Rigamonti, M. Valenza, C. Zuccato, L. Conti, J. Pritchard, C. Kooperberg, J. M. Olson, and E. Cattaneo Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses Hum. Mol. Genet., August 15, 2002; 11(17): 1953 - 1965. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
B. Ravikumar, R. Duden, and D. C. Rubinsztein Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy Hum. Mol. Genet., May 1, 2002; 11(9): 1107 - 1117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Wyttenbach, O. Sauvageot, J. Carmichael, C. Diaz-Latoud, A.-P. Arrigo, and D. C. Rubinsztein Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin Hum. Mol. Genet., May 1, 2002; 11(9): 1137 - 1151. [Abstract] [Full Text] [PDF]
|
|