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Sp1 and Huntington’s Disease

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Zinc Finger Proteins

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

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Abstract

Sp1, a triple C2H2 zinc finger protein, has been studied for more than two decades and biochemical features of the protein have been well documented. However, its biological roles in humans are still ambiguous. Recent studies on Huntington’s disease have shown that the mutant huntingtin proteins with expanded polyglutamine tracts interact with transcription factors, such as TFIID and Sp1, and have provided new insights into mechanisms of gene transcription as well as Huntington’s disease. Here, I describe aspects of Sp1 function in the context of Huntington’s disease research.

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References

  1. Vonsattel JP, DiFiglia M. Huntington’s disease. J Neuropathol Exp Neurol 1998; 57:369–384.

    PubMed  CAS  Google Scholar 

  2. Huntington’s disease collaborative research group. A novel gene containing a trinucleotide repeat that is unstable in Huntington’s disease chromosomes. Cell 1993; 72:971–983.

    Article  Google Scholar 

  3. Albin RL, Tagle DA. Genetics and molecular biology of Huntington’s disease. Trends Neurosci 1995; 18:11–14.

    Article  PubMed  CAS  Google Scholar 

  4. Warren ST. The expanding world of trinucleotide repeats. Science 1996; 271:1374–1375.

    Article  PubMed  CAS  Google Scholar 

  5. Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000; 23:217–47.

    Article  PubMed  CAS  Google Scholar 

  6. Reddy PS, Housman DE. The complex pathology of trinucleotide repeats. Curr Opin Cell Biol 1997; 9:364–372.

    Article  PubMed  CAS  Google Scholar 

  7. MacDonald ME et al. Huntington’s disease. Neuromolecular Med 2003; 4(1–2):7–20.

    Article  PubMed  CAS  Google Scholar 

  8. Strong TV et al. Widespread expression of the human and rat Huntington’s disease gene in brain and nonneural tissues. Nat Genet 1995; 5:259–263.

    Article  Google Scholar 

  9. Spargo E et al. Neuronal loss in the hippocampus in Huntington’s disease: Acomparison with HIV infection. J Neurol Neurosurg Psychiatry 1993; 56:487–491.

    Article  PubMed  CAS  Google Scholar 

  10. Byers RK et al. Huntington’s disease in children. Neuropathologic study of four cases. Neurology 1973; 23:561–569.

    PubMed  CAS  Google Scholar 

  11. Lange HG et al. Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci 1976; 28:401–425.

    Article  PubMed  CAS  Google Scholar 

  12. Landwehrmeyer GB et al. Huntington’s disease gene: Regional and cellular expression in brain of normal and affected individuals. Ann Neurol 1995; 37:218–230.

    Article  PubMed  CAS  Google Scholar 

  13. Ferrante RJ et al. Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum. J Neurosci 1997; 17:3052–3063.

    PubMed  CAS  Google Scholar 

  14. Jou YS, Myers RM. Evidence from antibody studies that the CAG repeat in the Huntington disease gene is expressed in the protein. Hum Mol Genet 1995; 4:465–469.

    Article  PubMed  CAS  Google Scholar 

  15. Trottier Y et al. Cellular localization of the Huntington’s disease protein and discrimination of the normal and mutated form. Nat Genet 1995; 10:104–110.

    Article  PubMed  CAS  Google Scholar 

  16. Cha J. Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 2000; 23:87–392.

    Article  Google Scholar 

  17. DiFiglia M et al. Huntington is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995; 14:1075–1081.

    Article  PubMed  CAS  Google Scholar 

  18. Wood JD et al. Partial characterization of the murine huntingtin and apparent variations in the subcellular localization of huntingtin in human, mouse and rat brain. Hum Mol Genet 1996; 5:481–487.

    Article  PubMed  CAS  Google Scholar 

  19. Yang W et al. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 2002; 11(23):2905–2917.

    Article  PubMed  CAS  Google Scholar 

  20. Chen S et al. Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci USA 2002; 99(18):11884–11889.

    Article  PubMed  CAS  Google Scholar 

  21. Kalchman MA et al. Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme. J Biol Chem 1996;271:19385–19394.

    Article  PubMed  CAS  Google Scholar 

  22. Burke JR et al. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med 1996; 2:347–350.

    Article  PubMed  CAS  Google Scholar 

  23. Sittler A et al. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 1998; 2:427–436.

    Article  PubMed  CAS  Google Scholar 

  24. Faber PW et al. Huntingtin interacts with the WW domain proteins. Hum Mol Genet 1998; 7:1463–1474.

    Article  PubMed  CAS  Google Scholar 

  25. Nasir J et al. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995; 81:811–823.

    Article  PubMed  CAS  Google Scholar 

  26. Zeitlin SZ et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995; 11:155–163.

    Article  PubMed  CAS  Google Scholar 

  27. Goldberg YP et al. Absence of the disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript. Hum Mol Genet 1996; 5:177–185.

    Article  PubMed  CAS  Google Scholar 

  28. Mangiarini L et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996; 87:493–506.

    Article  PubMed  CAS  Google Scholar 

  29. Burright EN et al. SCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 1996; 82:937–948.

    Article  Google Scholar 

  30. Kawaguchi Y et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1996; 8:221–228.

    Article  Google Scholar 

  31. Reddy PH et al. Bahvioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 1998; 20:198–202.

    Article  PubMed  CAS  Google Scholar 

  32. Hodgson JG et al. Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Hum Mol Genet 1996; 5:1875–1885.

    Article  PubMed  CAS  Google Scholar 

  33. Davies SW et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90:537–548.

    Article  PubMed  CAS  Google Scholar 

  34. Scherzinger E et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1998; 90:549–558.

    Article  Google Scholar 

  35. Klement S et al. Ataxin-1 nuclear localization and aggregation: Roll in polyglutamine-induced disease in SCA1 transgenic mice. Cell 1998; 95:41–53.

    Article  PubMed  CAS  Google Scholar 

  36. Kim M et al. Mutant huntingtin expression in clonal striatal cells: Dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci 1998; 19:964–973.

    Google Scholar 

  37. Saudou F et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95:55–66.

    Article  PubMed  CAS  Google Scholar 

  38. Huang CC et al. Amyloid formation by mutant huntingtin: Threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet 1998; 24:217–233.

    Article  PubMed  CAS  Google Scholar 

  39. Kazantsev A et al. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci USA 1999; 96:11404–11409.

    Article  PubMed  CAS  Google Scholar 

  40. McCampbell ARV et al. Colocalization of CBP with expanded polyglutamine containing androgen receptor. Am J Hum Genet 1999; 65(Suppl: A):106.

    Google Scholar 

  41. Ross CA et al. Polyglutamine pathogenesis. Philos Trans R Soc London B Biol Sci 1999; 354:1005–1011.

    Article  PubMed  CAS  Google Scholar 

  42. Steffan JS et al. The Huntington’s disease protein interacts with p53 and CBP and represses transcription. Proc Natl Acad Sci USA 2000; 97:6763–6768.

    Article  PubMed  CAS  Google Scholar 

  43. Boutell JM et al. Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 1999; 8:1647–1655.

    Article  PubMed  CAS  Google Scholar 

  44. Jones AL. The localization and interactions of huntingtin. Philos Trans R Soc Lond B Biol Sci 1999; 354:1021–1027.

    Article  PubMed  CAS  Google Scholar 

  45. Steffan JS et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001; 413:739–743.

    Article  PubMed  CAS  Google Scholar 

  46. Nucifora FC et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 2001; 291:2423–2428.

    Article  PubMed  CAS  Google Scholar 

  47. Zuccato C et al. Loss of Huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001; 293:493–498.

    Article  PubMed  CAS  Google Scholar 

  48. Augood SJ et al. Dopamine D1 and D2 receptor gene expression in the striatum in Huntington’s disease. Ann Neurol 1997; 42:215–221.

    Article  PubMed  CAS  Google Scholar 

  49. Cha J-HJ et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene. Proc Natl Acad Sci USA 1998; 95:6480–6485.

    Article  PubMed  CAS  Google Scholar 

  50. Berke JD et al. A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci 1998; 18:5301–5310.

    PubMed  CAS  Google Scholar 

  51. Gerfen CR et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990; 250:1429–1432.

    Article  PubMed  CAS  Google Scholar 

  52. Ona VO et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999; 399:263–267.

    Article  PubMed  CAS  Google Scholar 

  53. Luthi-Carter R et al. Decreased expression of striatal signalling genes in a mouse model of Huntington’s disease. Hum Mol Genet in press.

    Google Scholar 

  54. Dunah AW, Jeong H, Griffin A et al. Sp1 and TAF130 transciptional activity disrupted in early Huntington’s Disease. Science 2002; 296(5576):2238–2243.

    Article  PubMed  CAS  Google Scholar 

  55. Li SH, Cheng AL, Zhou H et al. Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 2002; 22(5):1277–1287.

    Article  PubMed  CAS  Google Scholar 

  56. Kadonaga JT et al. Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 1987; 51:1079–1090.

    Article  PubMed  CAS  Google Scholar 

  57. Dynan WS, Tjian R. Control of eukaryotic messanger RNA synthesis by sequence-specific DNA binding proteins. Nature 1985; 316:774–778.

    Article  PubMed  CAS  Google Scholar 

  58. Black AR et al. Sp1 and Kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 2001; 188:143–160.

    Article  PubMed  CAS  Google Scholar 

  59. Jackson SP, Tjian R. O-Glycosylation of eukaryotic transcription factors: Implications for mechanisms of transcriptional regulation. Cell 1988; 55:125–133.

    Article  PubMed  CAS  Google Scholar 

  60. Hagen G et al. Cloning by recognition site screening of two novel GT box binding proteins: A family of Sp1 related genes. Nucleic Acids Res 1992; 20:5519–5525.

    Article  PubMed  CAS  Google Scholar 

  61. Suske G. The Sp-family of transcription factors. Gene 1999; 238:291–300.

    Article  PubMed  CAS  Google Scholar 

  62. Sjottem E et al. The promoter activity of long terminal repeats of the HERV-H family of human retrovirus-like elements is critically dependent on Sp1 family proteins interacting with a GC/GT box located immediately 3′ to the TATA box. J Virol 1996; 70:188–198.

    PubMed  CAS  Google Scholar 

  63. Dennig J et al. An inhibitor domain in Sp3 regulates its glutamine-rich activation domains. EMBO J 1996; 15:5659–5667.

    PubMed  CAS  Google Scholar 

  64. Burley SK et al. Biochemistry and structural biology of transcription factor IID (TFIID). Annu Rev Biochem 1996; 65:769–799.

    Article  PubMed  CAS  Google Scholar 

  65. Chen JL et al. Assembly of recombinant TFIID reveals differential coactivator requirements for distinct transcriptional activators. Cell 1994; 79:93–105.

    Article  PubMed  CAS  Google Scholar 

  66. Hahn S. The role of TAFs in RNA polymerase II transcription. Cell 1998; 95:579–582.

    Article  PubMed  CAS  Google Scholar 

  67. Lee TI, Young, RA. Regulation of gene expression by TBP-associated proteins. Genes Dev 1998; 12:1398–1408.

    PubMed  CAS  Google Scholar 

  68. Verrijzer CP, Tjian R. TAFs mediate transcriptional activation and promoter selectivity. Trends Biochem Sci 1996; 21:338–342.

    Article  PubMed  CAS  Google Scholar 

  69. Struhl K, Moqtaderi Z. The TAFs in the HAT. Cell 1998; 94:1–4.

    Article  PubMed  CAS  Google Scholar 

  70. Bjorklund S et al. Global transcription regulators of eukaryotes. Cell 1999; 96:759–767.

    Article  PubMed  CAS  Google Scholar 

  71. Hampsey M. Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev 1998; 62:465–503.

    PubMed  CAS  Google Scholar 

  72. Sauer F, Tjian R. Mechanisms of transcriptional activation: Differences and similarities between yeast, Drosophila, and man. Curr Opin Genet Dev 1997; 7:176–181.

    Article  PubMed  CAS  Google Scholar 

  73. Moqtaderi Z et al. TBP-associated factors are not generally required for transcriptional activation in yeast. Nature 1996; 383:188–191.

    Article  PubMed  CAS  Google Scholar 

  74. Walker SS et al. Yeast TAFII145 required for transcription of G1/S cyclin genes and regulated by the cellular growth state. Cell 1997; 90:607–614.

    Article  PubMed  CAS  Google Scholar 

  75. Wang, EH, Tjian R. Promoter-selective transcriptional defect in cell cycle mutant ts13 rescued by hTAFII250. Science 1994; 263:811–814.

    Article  PubMed  CAS  Google Scholar 

  76. Wang, EH et al. TAFII250-dependent transcription of cyclin A is directed by ATF activator proteins. Genes Dev 1997; 11:2658–2669.

    PubMed  CAS  Google Scholar 

  77. Suzuki-Yagawa Y et al. The ts13 mutation in the TAF(II)250 subunit (CCG1) of TFIID directly affects transcription of D-type cyclin genes in cells arrested in G1 at the nonpermissive temperature. Mol Cell Biol 1997; 17:3284–3294.

    PubMed  CAS  Google Scholar 

  78. Holstege FC et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 1998; 95:717–728.

    Article  PubMed  CAS  Google Scholar 

  79. Tanese N et al. Molecular cloning and analysis of two subunits of the human TFIID complex: HTAFII130 and hTAFII100. Proc Natl Acad Sci USA 1996; 93:13611–13616.

    Article  PubMed  CAS  Google Scholar 

  80. Hoey T et al. Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators. Cell 1993; 72:247–260.

    Article  PubMed  CAS  Google Scholar 

  81. Rojo-Niersbach E et al. Genetic dissection of hTAF130 defines a hydrophobic surface required for interaction with glutamine-rich activators. J Biol Chem 1999; 274:33778–33784.

    Article  PubMed  CAS  Google Scholar 

  82. Saluja D et al. Distinct subdomains of human TAFII130 are required for interactions with glutamine-rich transcriptional activators. Mol Cell Biol 1998; 18:5734–5743.

    PubMed  CAS  Google Scholar 

  83. Ferreri K et al. The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. Proc Natl Acad Sci USA 1994; 91:1210–1213.

    Article  PubMed  CAS  Google Scholar 

  84. Wassarman DA et al. TAFII250: A transcription toolbox. J Cell Sci 2001; 114:2895–2902.

    PubMed  CAS  Google Scholar 

  85. O’Brien T et al. Different functional domains of TAFII250 modulate expression of distinct subsets of mammalian genes. Proc Natl Acad Sci USA 2000; 97:2456–2461.

    Article  PubMed  CAS  Google Scholar 

  86. Lee TI et al. Redundant roles for the TFIID and SAGA complexes in global transcription. Nature 2000; 405:701–704.

    Article  PubMed  CAS  Google Scholar 

  87. Mizzen CA et al. Transcription. New insights into an old modification. Science 2000; 289:2290–2291.

    Article  PubMed  CAS  Google Scholar 

  88. Strahl BD et al. The language of covalent modification. Nature 2000; 403:41–45.

    Article  PubMed  CAS  Google Scholar 

  89. Dunphy EL et al. Requirement for TAFII250 acetyltransferase activity in cell cycle progression. Mol Cell Biol 2000; 20:1134–1139.

    Article  PubMed  CAS  Google Scholar 

  90. Ryu H et. al. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci USA 2003; 100(7):4281–6.

    Article  PubMed  CAS  Google Scholar 

  91. Ferrante R et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 2003; 23(28):9418–9427.

    PubMed  CAS  Google Scholar 

  92. Kaczynski J et al. Sp1-and Kruppel-like transcription factors. Genome Biol 2003; 4(2):206–210.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. MassGeneral Institute for Neurodegenerative Disease Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Dimitri Krainc

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  1. Dimitri Krainc
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  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Shiro Iuchi

  2. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Natalie Kuldell

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Krainc, D. (2005). Sp1 and Huntington’s Disease. In: Iuchi, S., Kuldell, N. (eds) Zinc Finger Proteins. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27421-9_23

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