Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease
Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2002-06, Vol.296 (5576), p.2238-2243 |
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| creator | Dunah, Anthone W. Jeong, Hyunkyung Griffin, April Kim, Yong-Man Standaert, David G. Hersch, Steven M. Mouradian, M. Maral Young, Anne B. Tanese, Naoko Krainc, Dimitri |
| description | Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms. |
| doi_str_mv | 10.1126/science.1072613 |
| format | Article |
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Maral ; Young, Anne B. ; Tanese, Naoko ; Krainc, Dimitri</creator><creatorcontrib>Dunah, Anthone W. ; Jeong, Hyunkyung ; Griffin, April ; Kim, Yong-Man ; Standaert, David G. ; Hersch, Steven M. ; Mouradian, M. Maral ; Young, Anne B. ; Tanese, Naoko ; Krainc, Dimitri</creatorcontrib><description>Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1072613</identifier><identifier>PMID: 11988536</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Society for the Advancement of Science</publisher><subject>Animals ; Biological and medical sciences ; Brain ; Brain - metabolism ; Caudate nucleus ; Caudate Nucleus - metabolism ; Cell Death ; Cell Line ; Cell Nucleus - metabolism ; Cells, Cultured ; Corpus Striatum - cytology ; Corpus Striatum - embryology ; Corpus Striatum - metabolism ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease ; DNA ; DNA - metabolism ; DNA-Binding Proteins - chemistry ; DNA-Binding Proteins - metabolism ; Down-Regulation ; Gene Expression Regulation ; Genes ; Genetic aspects ; Grade 1 ; Grade 4 ; Hippocampus ; Humans ; Huntingtin Protein ; Huntington Disease - genetics ; Huntington Disease - metabolism ; Huntington's chorea ; Huntington's disease ; Medical sciences ; Mice ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins - chemistry ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Nervous system ; Neurology ; Neurons ; Neurons - physiology ; Nuclear Proteins - chemistry ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nucleoproteins ; Patients ; Peptides ; Promoter Regions, Genetic ; Proteins ; Rats ; Receptors, Dopamine D2 - genetics ; Social interaction ; Solubility ; Sp1 Transcription Factor - chemistry ; Sp1 Transcription Factor - metabolism ; TATA-Binding Protein Associated Factors ; Transcription Factor TFIID ; Transcription Factors - chemistry ; Transcription Factors - metabolism ; Transcription, Genetic ; Transfection ; Transgenic animals ; Trinucleotide Repeat Expansion ; Two-Hybrid System Techniques</subject><ispartof>Science (American Association for the Advancement of Science), 2002-06, Vol.296 (5576), p.2238-2243</ispartof><rights>Copyright 2002 American Association for the Advancement of Science</rights><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2002 American Association for the Advancement of Science</rights><rights>COPYRIGHT 2002 American Association for the Advancement of Science</rights><rights>Copyright American Association for the Advancement of Science Jun 21, 2002</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c775t-71b2ea14148cb29a6692c61771b0850515841afda240c1a0fc7711ce67ea669d3</citedby><cites>FETCH-LOGICAL-c775t-71b2ea14148cb29a6692c61771b0850515841afda240c1a0fc7711ce67ea669d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3077126$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3077126$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13742323$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11988536$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dunah, Anthone W.</creatorcontrib><creatorcontrib>Jeong, Hyunkyung</creatorcontrib><creatorcontrib>Griffin, April</creatorcontrib><creatorcontrib>Kim, Yong-Man</creatorcontrib><creatorcontrib>Standaert, David G.</creatorcontrib><creatorcontrib>Hersch, Steven M.</creatorcontrib><creatorcontrib>Mouradian, M. Maral</creatorcontrib><creatorcontrib>Young, Anne B.</creatorcontrib><creatorcontrib>Tanese, Naoko</creatorcontrib><creatorcontrib>Krainc, Dimitri</creatorcontrib><title>Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Caudate nucleus</subject><subject>Caudate Nucleus - metabolism</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Cell Nucleus - metabolism</subject><subject>Cells, Cultured</subject><subject>Corpus Striatum - cytology</subject><subject>Corpus Striatum - embryology</subject><subject>Corpus Striatum - metabolism</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Disease</subject><subject>DNA</subject><subject>DNA - metabolism</subject><subject>DNA-Binding Proteins - chemistry</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Down-Regulation</subject><subject>Gene Expression Regulation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Grade 1</subject><subject>Grade 4</subject><subject>Hippocampus</subject><subject>Humans</subject><subject>Huntingtin Protein</subject><subject>Huntington Disease - genetics</subject><subject>Huntington Disease - metabolism</subject><subject>Huntington's chorea</subject><subject>Huntington's disease</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Nerve Tissue Proteins - chemistry</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Nervous system</subject><subject>Neurology</subject><subject>Neurons</subject><subject>Neurons - physiology</subject><subject>Nuclear Proteins - chemistry</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nucleoproteins</subject><subject>Patients</subject><subject>Peptides</subject><subject>Promoter Regions, Genetic</subject><subject>Proteins</subject><subject>Rats</subject><subject>Receptors, Dopamine D2 - genetics</subject><subject>Social interaction</subject><subject>Solubility</subject><subject>Sp1 Transcription Factor - chemistry</subject><subject>Sp1 Transcription Factor - metabolism</subject><subject>TATA-Binding Protein Associated Factors</subject><subject>Transcription Factor TFIID</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>Transfection</subject><subject>Transgenic animals</subject><subject>Trinucleotide Repeat Expansion</subject><subject>Two-Hybrid System Techniques</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0kFr2zAUB3AzNtas23mXMcxg6w51qyfZknxMszYNhIXRbFehyHJQcORUkkfz7acQs5IRRtBB8N5PTyD9k-Q9oCsATK-9MtoqfQWIYQrkRTIAVBZZiRF5mQwQIjTjiBVnyRvvVwjFXkleJ2cAJecFoYPkx8MGUmmrdD68m0yAoHTupPXKmU0wrZVNOlTB_DZhm34z3nWboKvU2PRWumab3nc2GLsMrb3wu76WXr9NXtWy8fpdv58nP-9u56P7bDobT0bDaaYYK0LGYIG1hBxyrha4lJSWWFFgsY54gQooeA6yriTOkQKJ6ngMQGnK9M5W5Dy52M_duPax0z6ItfFKN420uu28YDnJKWBOovzyXwk8x5gVLMJP_8BV27n4CF5gIBQBZiiiyz1aykYLY-s2OKmW2monm9bq2sTykPN4N2E48uwIj6vSa6OO-a8HPpKgn8JSdt6LycP3k-ns18n0Znwq5ePpAb08RlXbNHqpRfzu0eyAX--5cq33Ttdi48xauq0AJHZxFn2cRR_neOJj_yHdYq2rZ9_nN4LPPZBeyaaO2VXGPzvCckzwbtCHvVv50Lq_fYJiqDAlfwDQj__b</recordid><startdate>20020621</startdate><enddate>20020621</enddate><creator>Dunah, Anthone W.</creator><creator>Jeong, Hyunkyung</creator><creator>Griffin, April</creator><creator>Kim, Yong-Man</creator><creator>Standaert, David G.</creator><creator>Hersch, Steven M.</creator><creator>Mouradian, M. 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April</au><au>Kim, Yong-Man</au><au>Standaert, David G.</au><au>Hersch, Steven M.</au><au>Mouradian, M. Maral</au><au>Young, Anne B.</au><au>Tanese, Naoko</au><au>Krainc, Dimitri</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2002-06-21</date><risdate>2002</risdate><volume>296</volume><issue>5576</issue><spage>2238</spage><epage>2243</epage><pages>2238-2243</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>11988536</pmid><doi>10.1126/science.1072613</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2002-06, Vol.296 (5576), p.2238-2243 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743461283 |
| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Animals Biological and medical sciences Brain Brain - metabolism Caudate nucleus Caudate Nucleus - metabolism Cell Death Cell Line Cell Nucleus - metabolism Cells, Cultured Corpus Striatum - cytology Corpus Striatum - embryology Corpus Striatum - metabolism Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease DNA DNA - metabolism DNA-Binding Proteins - chemistry DNA-Binding Proteins - metabolism Down-Regulation Gene Expression Regulation Genes Genetic aspects Grade 1 Grade 4 Hippocampus Humans Huntingtin Protein Huntington Disease - genetics Huntington Disease - metabolism Huntington's chorea Huntington's disease Medical sciences Mice Mice, Transgenic Mutation Nerve Tissue Proteins - chemistry Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nervous system Neurology Neurons Neurons - physiology Nuclear Proteins - chemistry Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleoproteins Patients Peptides Promoter Regions, Genetic Proteins Rats Receptors, Dopamine D2 - genetics Social interaction Solubility Sp1 Transcription Factor - chemistry Sp1 Transcription Factor - metabolism TATA-Binding Protein Associated Factors Transcription Factor TFIID Transcription Factors - chemistry Transcription Factors - metabolism Transcription, Genetic Transfection Transgenic animals Trinucleotide Repeat Expansion Two-Hybrid System Techniques |
| title | Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T06%3A23%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Sp1%20and%20TAFII130%20Transcriptional%20Activity%20Disrupted%20in%20Early%20Huntington's%20Disease&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Dunah,%20Anthone%20W.&rft.date=2002-06-21&rft.volume=296&rft.issue=5576&rft.spage=2238&rft.epage=2243&rft.pages=2238-2243&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.1072613&rft_dat=%3Cgale_proqu%3EA88612372%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213601270&rft_id=info:pmid/11988536&rft_galeid=A88612372&rft_jstor_id=3077126&rfr_iscdi=true |