Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Abstract

Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial. Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial. Huntington disease (HD) 2The abbreviations used are: HD, Huntington disease; Htt, mutant huntingtin; WT, wild type; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyltetrazolium bromide; LDH, lactate dehydrogenase; eGFP, enhanced green fluorescent protein; RNAi, RNA interference; 3-NP, 3-nitropropionate; siRNA, small interfering RNA.2The abbreviations used are: HD, Huntington disease; Htt, mutant huntingtin; WT, wild type; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyltetrazolium bromide; LDH, lactate dehydrogenase; eGFP, enhanced green fluorescent protein; RNAi, RNA interference; 3-NP, 3-nitropropionate; siRNA, small interfering RNA. is a fatal hereditary neurodegenerative disorder characterized by progressive motor and cognitive deficits caused by neuronal dysfunction and degeneration affecting selected populations of neurons. The genetic defect responsible for HD is a CAG repeat expansion in exon 1 of the HD gene leading to the expression of a mutant huntingtin (Htt) protein containing an abnormally long polyglutamine sequence (1Paulson H.L. Fischbeck K.H. Annu. Rev. Neurosci. 1996; 19: 79-107Crossref PubMed Scopus (299) Google Scholar). Direct interactions between mutant Htt and a variety of transcription factors have been identified, which may significantly contribute to the pathogenesis of HD (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar, 3Nucifora F.C.J. Sasaki M. Peters M.F. Huang H. Cooper J.K. Yamada M. Takahashi H. Tsuji S. Troncoso J. Dawson V.L. Dawson T.M. Ross C.A. Science. 2001; 291: 2423-2428Crossref PubMed Scopus (936) Google Scholar). Gene microarray studies have indicated that selective transcriptional alterations occur early in HD (4Luthi-Carter R. Strand A. Peters N.L. Solano S.M. Hollingsworth Z.R. Menon A.S. Frey A.S. Spektor B.S. Penney E.B. Schilling G. Ross C.A. Borchelt D.R. Tapscott S.J. Young A.B. Cha J.H. Olson J.M. Hum. Mol. Genet. 2000; 22: 1259-1271Crossref Scopus (616) Google Scholar), consistent with transcriptional dysregulation (5Steffan J.S. Bodai L. Pallos J. Poelman M. McCampbell A. Apostol B.L. Kazantsev A. Schmidt E. Zhu Y.Z. Greenwald M. Kurokawa R. Housman D.E. Jackson G.R. Marsh J.L. Thompson L.M. Nature. 2001; 413: 739-743Crossref PubMed Scopus (1039) Google Scholar, 6Hersch S.M. Curr. Opin. Neurol. 2003; 16: 501-506PubMed Google Scholar, 7Steffan J.S. Agrawal N. Pallos J. Rockabrand E. Trotman L.C. Slepko N. Illes K. Lukacsovich T. Zhu Y.Z. Cattaneo E. Pandolfi P.P. Thompson L.M. Marsh J.L. Science. 2004; 304: 100-104Crossref PubMed Scopus (553) Google Scholar). Many of the altered genes contain binding sites for Sp1, which we recently demonstrated to interact with Htt in a polyglutamine length-dependent manner (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar). Sp1 is a zinc-finger domain (C terminus) transcriptional activator (8Bouwman P. Philipsen S. Mol. Cell. Endocrinol. 2002; 195: 27-38Crossref PubMed Scopus (397) Google Scholar) that has been implicated in the expression of many genes in concert with other transcription factors, including the TAFII family (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar), CREB (3Nucifora F.C.J. Sasaki M. Peters M.F. Huang H. Cooper J.K. Yamada M. Takahashi H. Tsuji S. Troncoso J. Dawson V.L. Dawson T.M. Ross C.A. Science. 2001; 291: 2423-2428Crossref PubMed Scopus (936) Google Scholar, 9Liu Y.W. Tseng H.P. Chen L.C. Chen B.K. Chang W.C. J. Immunol. 2003; 171: 821-828Crossref PubMed Scopus (96) Google Scholar), nuclear factor-κB (10Fridmacher V. Kaltschmidt B. Goudeau B. Ndiaye D. Rossi F.M. Pfeiffer J. Kaltschmidt C. Israel A. Memet S. J. Neurosci. 2003; 23: 9403-9408Crossref PubMed Google Scholar), and vesicular endothelial growth factor receptor-2 (VEGFR-2) (11Tanaka T. Kanai H. Sekiguchi K. Aihara Y. Yokoyama T. Arai M. Kanda T. Nagai R. Kurabayashi M. J. Mol. Cell Cardiol. 2000; 32: 1955-1967Abstract Full Text PDF PubMed Scopus (106) Google Scholar, 12Meissner M. Stein M. Urbich C. Reisinger K. Suske G. Staels B. Kaufmann R. Gille J. Circ. Res. 2004; 20: 324-332Crossref Scopus (97) Google Scholar). Sp1-mediated processes include aberrant transcriptional modulation of dopamine receptor genes, neurodegeneration (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar, 13Li S.H. Cheng A.L. Zhou H. Lam S. Rao M. Li H. Li X.J. Mol. Cell. Biol. 2002; 22: 1277-1287Crossref PubMed Scopus (281) Google Scholar, 14Ryu H. Lee J. Zaman K. Kubilis J. Ferrante R.J. Ross B.D. Neve R. Ratan R.R. J. Neurosci. 2003; 23: 3597-3606Crossref PubMed Google Scholar), and inflammatory processes (12Meissner M. Stein M. Urbich C. Reisinger K. Suske G. Staels B. Kaufmann R. Gille J. Circ. Res. 2004; 20: 324-332Crossref Scopus (97) Google Scholar, 15Fiuza C. Bustin M. Talwar S. Tropea M. Gerstenberger E. Shelhamer J.H. Suffredini A.F. Blood. 2003; 101: 2652-2660Crossref PubMed Scopus (644) Google Scholar), which are important in the pathogenesis of HD. However, various in vitro studies have implicated Sp1 as being prosurvival (16Li F. Altieri D.C. Biochem. J. 1999; 344: 305-311Crossref PubMed Scopus (288) Google Scholar, 17Tanaka T. Kurabayashi M. Aihara Y. Ohyama Y. Nagai R. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 392-401Crossref PubMed Scopus (39) Google Scholar) or prodeath (18Liu Y.W. Arakawa T. Yamamoto S. Chang W.C. Biochem. J. 1997; 324: 133-140Crossref PubMed Scopus (42) Google Scholar, 19Xiao S. Marshak-Rothstein A. Ju S.T. Eur. J. Immunol. 2001; 31: 3339-3348Crossref PubMed Scopus (10) Google Scholar), or involved in neurodegeneration (10Fridmacher V. Kaltschmidt B. Goudeau B. Ndiaye D. Rossi F.M. Pfeiffer J. Kaltschmidt C. Israel A. Memet S. J. Neurosci. 2003; 23: 9403-9408Crossref PubMed Google Scholar, 14Ryu H. Lee J. Zaman K. Kubilis J. Ferrante R.J. Ross B.D. Neve R. Ratan R.R. J. Neurosci. 2003; 23: 3597-3606Crossref PubMed Google Scholar). Whereas interactions between Sp1 and mutant huntingtin appear to be deleterious at the molecular level (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar), we have also demonstrated that blocking Sp1 using mithramycin A dramatically prolonged survival in a mouse model of HD (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar). the effects of mutant huntingtin Sp1 may be by the effects of Sp1 in HD In we the of Sp1 in the found in three Htt neuronal cell expressing either or mutant Htt, neurodegeneration induced by mutant Htt or in and in using primary neurons and mice by Sp1 heterozygous knock-out and or transgenic mouse of HD. We found that Sp1 is induced by as as by the of mutant Htt in vitro and in caused by mutant Htt or was with increased Sp1 levels in the and genetic of Sp1 using mithramycin A, or RNA toxicity induced by either or mutant Sp1 effects with the down mutant Htt We also found that knocking down Sp1 was in primary striatal neurons as as mice the A a in mutant huntingtin expression in the mutant mice the prolonged survival of HD mice. studies suggest that of Sp1 in to mutant huntingtin and that of Sp1 is Cell cell containing an protein with the of Htt or with at the B.L. Kazantsev A. S. Illes K. Pallos J. Bodai L. Slepko N. Hersch S. Housman D.E. Marsh J.L. Thompson L.M. S. A. 2003; PubMed Scopus Google Scholar) were by The cells were in containing and 1 expression was induced with neuronal were Sp1 heterozygous knock-out mice M. A. P. F. Philipsen S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) by The crossed with or transgenic mice, and neurons mice with genetic were by B. G. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). were in and tissue at a of The neurons were in with with was with containing cells were in for than knock-out mice M. A. P. F. Philipsen S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) were with transgenic mouse of HD, and The HD transgenic mice CAG exon 1 and of the HD gene by the mouse G. K. T. Cooper J.K. Ross C.A. Borchelt D.R. Hum. Mol. Genet. 1999; PubMed Google Scholar). The mice exon 1 of the HD gene with CAG L. K. M. B. A. C. M. Y. H. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of the mice are a mouse or neuronal was by to its was in and in transgenic with Sp1 knock-out mice. the survival in were WT, WT, and the were WT, WT, and were in with the for the and the of and the The mice were of and for the of their survival was for early and as R.J. Kubilus J.K. Lee J. Ryu H. A. B. Smith K. Ratan R.R. R. Hersch S.M. J. Neurosci. 2003; 23: PubMed Google Scholar). were for were the lactate J. Neurosci. 20: PubMed Scopus Google Scholar, D. J. Neurosci. PubMed Google Scholar) and the bromide; J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) were in The and the cells. was for and cells for in cell were for studies the PC12 cells and the primary striatal neurons were with for with and mithramycin A for to the and were to the for the and and Htt cell were and for at using Sp1 was with and Htt were by for primary striatal neurons, mutant Htt and Sp1 were with and Htt in HD mice brain were by using by the (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar). were with and were and in were with to the of was an using the the of the in the mouse tissue were using a was the was characterized by nuclear or including and nuclear using and a the of was by the V. Mol. Biol. 2001; Google Scholar). The and of nuclear was using the J. PubMed Scopus Google Scholar) in and In a Htt selected were with a and by with Htt the and mice and crossed with Sp1 heterozygous knock-out mice, was using of the and cell in were to the brain of mice and for and mouse brain tissue were or in containing and of protein were for Sp1 and mutant Htt by proteins were and by to proteins were with Sp1 or polyglutamine expansion the was by a to that protein was in was using a and with a were as of the or mouse Sp1 RNA Sp1 small interfering RNA was used to the Sp1 sequence The of Sp1 were to the and to a the sequence to that genes of the were of Sp1 were the cells were with and by to the Sp1 gene cell in the cells was in to the of Sp1 by primary striatal neurons, and mouse were to the transcription of RNA was with a for studies used a to the of were 1 at of for for 1 and for 1 used were Sp1 Htt and expression levels for were to using the 2001; PubMed Scopus Google Scholar). or were for are as of by the for survival data were using the K. M. K. B. A 1996; Scholar) and survival The survival were for were a of and in was of a Htt Sp1 indicated that Htt and Sp1 levels were enhanced with of Htt expression in PC12 in the demonstrated increased levels of Sp1 in cells that may be or involved in the alterations of Sp1 in and cells increased Sp1 cells a and cells a enhancement was also mouse at the of a for that the Sp1 levels are mutant Htt and in increased Sp1 levels in primary striatal neuronal and transgenic mice of mutant Htt with Sp1 was also in the of primary striatal neurons mice The binding of Sp1, by was also enhanced in mouse in with the increased Sp1 protein levels and enhanced Sp1 has also been that Sp1 levels are increased in brain in the early of HD (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar). the of mutant Htt in vitro and in with increased Sp1 levels and Sp1 Cell an of pathology HD in M.F. E. Ferrante R.J. J.M. E. R. J. Neurosci. PubMed Google Scholar). cells cell as significantly increased cell death in PC12 cells expressing were to to expression not the effects of were in and the significantly for the cells which that neuronal cells to To Sp1 in the of mutant Htt, we the effects of and genetic of Sp1 using mithramycin A and Sp1 RNAi, A is an that inhibits gene expression by blocking Sp1 binding to of We the effects of mithramycin A neuronal cell death in and cells in the of induced cell toxicity was by mithramycin A in and cells A toxicity in a manner in and cells. effects of mithramycin A (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar) were in cells not In in Sp1 levels were in mithramycin cells consistent with the of mithramycin A as a of that mithramycin A other in to Sp1, we also Sp1 using Sp1 cells are by the neuronal cell death was in in cell death were between and sequence Sp1 neuronal cell death induced by In the of siRNA, Sp1 levels were significantly as by in cells and by in and the in Sp1 levels caused by was not that the alterations in toxicity in with Sp1 gene Sp1 also significantly the expression of by using was when mithramycin was to the cell with Sp1 not that Sp1 and mithramycin a data suggest that either blocking gene expression by mithramycin A or Sp1 gene expression by Sp1 and neuronal cell death. Sp1 Gene in HD Sp1 an important in neurodegeneration in HD, primary striatal neurons WT, Sp1 heterozygous HD and Sp1 heterozygous knock-out mice crossed with HD transgenic mice were as in mice the the cells have a in are to the and and are by with the and of with by are HD transgenic and Sp1 heterozygous and HD transgenic with Sp1 heterozygous knock-out mice as neurons the The of neurodegeneration in primary neurons was in neuronal death between and neurons were at and neurodegeneration was at at the in neuronal death between and neurons is and The neurodegeneration in primary striatal neurons genetic was and neuronal death was significantly increased in neurons not in Sp1 or Sp1 crossed with neurons. alterations were when the neurons were with for the are to 3-NP, the effects of are in neurons. Sp1 gene neurons toxicity mutant toxicity and of mutant Htt, by with polyglutamine expansion were in neurons mouse crossed with Sp1 heterozygous knock-out mouse in by Our data that the neurodegeneration in primary striatal neurons HD transgenic mouse is by the Sp1 gene that Sp1 may be deleterious in HD. of Sp1 gene expression and transcriptional activity was in the Sp1 heterozygous knock-out mouse we Sp1 mRNA levels in neurons and mouse using with Sp1 Sp1 mRNA levels significantly in primary neurons and mouse by Sp1 gene in neurons and in Whereas Sp1 mRNA levels increased in mice with mouse the in Sp1 expression of the crossed mice was significantly we the expression of Sp1 protein in primary neurons and mouse using Sp1 protein levels were in the crossed including with or as as in Sp1 heterozygous knock-out were the in crossed with the in crossed with and the in The alterations in Sp1 protein levels in the Sp1 heterozygous knock-out and crossed mice were consistent between neuronal and mouse Sp1 levels were in mouse not in neurons in the crossed mice with Sp1 heterozygous knock-out mice. when Sp1 heterozygous knock-out mice were crossed with HD transgenic mice, a to the Sp1 M. A. P. F. Philipsen S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), at a in the Sp1 exon for the and the We that the of Sp1 is not consistent with by other Jackson R. Cell. Full Text PDF PubMed Scopus Google Scholar, G. S. M. Suske G. J. PubMed Scopus Google Scholar). transcriptional activity was by in neurons Sp1 heterozygous knock-out mouse as by a transcriptional when neurons were with containing Sp1 binding in the levels of the were not in the crossed with Sp1 heterozygous knock-out mice that is to a of The increased of Sp1 for resulting in the may be caused by between the and the In addition, we that Sp1 gene caused in and protein levels in neurons and in data the Sp1 at the and Sp1 Gene the of HD of Sp1 heterozygous knock-out mice crossed with and mice were The Sp1 heterozygous knock-out crossed with and mice were for in survival of the or Sp1 heterozygous knock-out mice the of the The Sp1 heterozygous knock-out crossed with mice significantly longer than the HD transgenic with mice, and with the mice. in crossed mice with the was not with HD transgenic mice not The increased by Sp1 gene in the HD transgenic mice the effects of of Sp1 in Htt and mutant Htt gene expression were in the Sp1 heterozygous knock-out mice crossed with mice. Htt be by in the of HD transgenic and crossed mice in and at the of three We the and of Htt with and by the or nuclear We found in the of between mice and Sp1 heterozygous knock-out mice crossed with mice was in the and of nuclear Htt by Sp1 in and consistent with the in mice with mithramycin A (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar). Htt gene expression was by using polyglutamine expansion and by using a the in exon 1 Htt expression by and that Sp1 gene to mutant Htt by and Htt mRNA by were not was in Htt gene expression not A was also in by by with the Htt not The in Htt expression was not in the crossed mice, Sp1 significantly the expression of mutant Htt in the PC12 model Sp1 gene in HD transgenic mice may have a small Htt which contribute to the in the of crossed mice. In we have the of Sp1 in HD using and transgenic that Sp1 is in the of mutant Htt and its is Our was to the effects of mutant Htt and the Sp1 levels in PC12 assess Sp1 levels in primary neurons and transgenic mice, and Sp1 by siRNA, mithramycin A, and using Sp1 heterozygous knock-out mice crossed with HD transgenic mice. the we for effects the expression of genes as as of Htt and We found that mutant Htt or enhanced Sp1 levels and that of Sp1 the survival of and Sp1 was with alterations in Htt gene D2 and did not significantly In was that molecular interactions between Sp1 and mutant huntingtin may be deleterious (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar). However, of Sp1 binding sites by mithramycin A is the that has been to the model of HD (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar). Our studies by Sp1 modulation and mouse of HD. of consistently that or blocking Sp1 is in the of mutant Sp1 may be by aberrant interactions with mutant data that is by the of Sp1 Our data Sp1 as a in HD. The of transcriptional dysfunction to neurodegeneration in HD gene expression and have a of the of genes in vitro Jackson Mol. Cell. Biol. PubMed Scopus Google Scholar). Our the of mutant and Sp1 and for a of Sp1 in HD Sp1 gene in cell by an between Sp1 and which Sp1 binding to the B.L. Kazantsev A. S. Illes K. Pallos J. Bodai L. Slepko N. Hersch S. Housman D.E. Marsh J.L. Thompson L.M. S. A. 2003; PubMed Scopus Google Scholar). Sp1-mediated of contribute to the In addition, Sp1 not and knocking the Sp1 in mice in effects 3-NP, Our cell that enhanced Sp1 levels in HD is involved in In cell the transgenic mouse an in and of disease The of of the effects in the genetic were of Sp1 were the of effects are than their of Sp1 is (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar). The for a in mutant huntingtin expression caused by Sp1 gene in the of huntingtin transgenic mice in and for the prolonged survival of HD mice which may the Sp1 the huntingtin C. Schmidt T. G. Res. Mol. Res. 2001; PubMed Scopus Google Scholar). However, was in in mouse a of huntingtin mutant huntingtin in and Htt levels were in mice with mithramycin A (20Ferrante R.J. Ryu H. Kubilus J.K. D'Mello S. Sugars K.L. Lee J. Lu P. Smith K. Browne S. Beal M.F. B.S. S. D.C. B. Ratan R.R. J. Neurosci. 2004; PubMed Scopus Google Scholar). Our data suggested that modulation of Sp1-mediated mutant Htt expression is to the primary in in Sp1 has been implicated in the expression of many genes, with its binding sites in in which the level of expression and in cell Jackson Mol. Cell. Biol. PubMed Scopus Google Scholar). was Sp1 may be genes as involved in A. N. M. D. K. B. J. S. E. M. 1997; Scopus Google Scholar) or receptor gene To gene transcription in Sp1 heterozygous knock-out crossed with HD transgenic mouse we the D2 dopamine receptor which is by Sp1 and which is reduced in the in HD S.J. Neurol. 1997; PubMed Scopus Google Scholar, J.H. L. Penney Young A.B. S. A. PubMed Scopus Google Scholar). in Sp1 levels were with D2 receptor mRNA in HD transgenic mice in However, when D2 gene containing the sequence of Sp1 binding were mutant Htt neurons, D2 receptor expression was enhanced (2Dunah A.W. Jeong H. Griffin A. Kim Y.M. Standaert D.G. Hersch S.M. Mouradian M.M. Young A.B. Tanese N. Krainc D. Science. 2002; 296: 2238-2243Crossref PubMed Scopus (583) Google Scholar). Our are consistent with Sp1 as a of the D2 dopamine receptor gene T. Mouradian M.M. J. Biol. Full Text PDF PubMed Google Scholar, S. Y. Lee S.H. Kim Y.M. Mouradian M.M. S. A. 2001; PubMed Scopus Google Scholar) and with Sp1 transcription to a gene to be in HD. transcription factors, in to Sp1, contribute to the of gene expression caused by aberrant interactions with Htt has as which to neurons to other for Our data that a transcriptional Sp1 and other transcription factors in that may also contribute to neuronal death. of Sp1 to be its with Sp1 and processes in for Sp1 in HD Sp1 expression of S. K. G. Res. Mol. Res. 2002; PubMed Scopus Google Scholar, D. G. S. M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). be by the Sp1 the E. L. E. H.P. P. S. M. N. F. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar), as as by J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Sp1 or expression may a in HD by a of deleterious We for the Sp1 mouse We Krainc for and and