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Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin
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 carryi...
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Published in: | Human molecular genetics 1999-09, Vol.8 (9), p.1647-1655 |
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description | 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 immunohisto-chemical 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 immuno-reactivity 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. |
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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 immunohisto-chemical 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 immuno-reactivity 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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/8.9.1647</identifier><identifier>PMID: 10441327</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Acetyltransferases - metabolism ; Amino Acid Sequence ; Animals ; Biological and medical sciences ; Brain - metabolism ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Escherichia coli - metabolism ; Fundamental and applied biological sciences. Psychology ; Histone Acetyltransferases ; Histone Deacetylases ; Humans ; Huntingtin Protein ; Huntington Disease - genetics ; Immunohistochemistry ; Medical sciences ; Molecular and cellular biology ; Molecular genetics ; Molecular Sequence Data ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Neurology ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nuclear Receptor Co-Repressor 1 ; Rats ; Recombinant Proteins - metabolism ; Repressor Proteins - metabolism ; Saccharomyces cerevisiae Proteins ; Sequence Alignment ; Transcription Factors - metabolism ; Transcription. Transcription factor. Splicing. 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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 immunohisto-chemical 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 immuno-reactivity 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.</description><subject>Acetyltransferases - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - metabolism</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Escherichia coli - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Histone Acetyltransferases</subject><subject>Histone Deacetylases</subject><subject>Humans</subject><subject>Huntingtin Protein</subject><subject>Huntington Disease - genetics</subject><subject>Immunohistochemistry</subject><subject>Medical sciences</subject><subject>Molecular and cellular biology</subject><subject>Molecular genetics</subject><subject>Molecular Sequence Data</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neurology</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Nuclear Receptor Co-Repressor 1</subject><subject>Rats</subject><subject>Recombinant Proteins - metabolism</subject><subject>Repressor Proteins - metabolism</subject><subject>Saccharomyces cerevisiae Proteins</subject><subject>Sequence Alignment</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription. 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Rna processing</subject><subject>Yeasts</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNqF0c9rFDEUwPEgil1bb55lkGIvnW1-TTI5ltZ2i4WqVBEvIZN5002dnVnzMmj_e7PsUsWLp8DLh0fIl5BXjM4ZNeJkubo7qedmzpTUT8iMSUVLTmvxlMyoUbJUhqo98gLxntJshH5O9hiVkgmuZySeNhCjG1JxNSSIzqcwDliMXXGbp-hjWG8mri8-wToC4hiLD3FMELL6GdKySEsoFtOQwnCXxuEIi_OA4BCKSxhgY9vJp-NHEoYD8qxzPcLL3blPPl-8uz1blNc3l1dnp9ellxVNpeGmE9JzxVXjHfMVb1vtK6idaoxTldGK176p6xacltAC61grOiOEY11lWrFP3m73ruP4YwJMdhXQQ9-7AcYJrTKm4hVX_4VMC8m14Rm--Qfej1PMn4OWM5ZZflRGx1vk44gYobPrGFYuPlhG7aaYzcVsbY3dFMv89W7n1Kyg_QtvE2VwuAMOveu7nMUH_OOMFBU3mZVbFjDBr8drF79bpYWu7OLrN_v-ov7CzsVHy8RvjRuuvw</recordid><startdate>19990901</startdate><enddate>19990901</enddate><creator>Boutell, Jonathan M.</creator><creator>Thomas, Philip</creator><creator>Neal, James W.</creator><creator>Weston, Victoria J.</creator><creator>Duce, James</creator><creator>Harper, Peter S.</creator><creator>Lesley Jones, A.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19990901</creationdate><title>Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin</title><author>Boutell, Jonathan M. ; Thomas, Philip ; Neal, James W. ; Weston, Victoria J. ; Duce, James ; Harper, Peter S. ; Lesley Jones, A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-929f34c2626bca1c52dd7c5e8a6b9a6597628cb88dea74ede1f1d3f933a1f59d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Acetyltransferases - metabolism</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Brain - metabolism</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Escherichia coli - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Histone Acetyltransferases</topic><topic>Histone Deacetylases</topic><topic>Humans</topic><topic>Huntingtin Protein</topic><topic>Huntington Disease - genetics</topic><topic>Immunohistochemistry</topic><topic>Medical sciences</topic><topic>Molecular and cellular biology</topic><topic>Molecular genetics</topic><topic>Molecular Sequence Data</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neurology</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nuclear Receptor Co-Repressor 1</topic><topic>Rats</topic><topic>Recombinant Proteins - metabolism</topic><topic>Repressor Proteins - metabolism</topic><topic>Saccharomyces cerevisiae Proteins</topic><topic>Sequence Alignment</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription. Transcription factor. Splicing. Rna processing</topic><topic>Yeasts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boutell, Jonathan M.</creatorcontrib><creatorcontrib>Thomas, Philip</creatorcontrib><creatorcontrib>Neal, James W.</creatorcontrib><creatorcontrib>Weston, Victoria J.</creatorcontrib><creatorcontrib>Duce, James</creatorcontrib><creatorcontrib>Harper, Peter S.</creatorcontrib><creatorcontrib>Lesley Jones, A.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boutell, Jonathan M.</au><au>Thomas, Philip</au><au>Neal, James W.</au><au>Weston, Victoria J.</au><au>Duce, James</au><au>Harper, Peter S.</au><au>Lesley Jones, A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Human Molecular Genetics</addtitle><date>1999-09-01</date><risdate>1999</risdate><volume>8</volume><issue>9</issue><spage>1647</spage><epage>1655</epage><pages>1647-1655</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>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 immunohisto-chemical 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 immuno-reactivity 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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>10441327</pmid><doi>10.1093/hmg/8.9.1647</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Acetyltransferases - metabolism Amino Acid Sequence Animals Biological and medical sciences Brain - metabolism Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Escherichia coli - metabolism Fundamental and applied biological sciences. Psychology Histone Acetyltransferases Histone Deacetylases Humans Huntingtin Protein Huntington Disease - genetics Immunohistochemistry Medical sciences Molecular and cellular biology Molecular genetics Molecular Sequence Data Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurology Nuclear Proteins - genetics Nuclear Proteins - metabolism Nuclear Receptor Co-Repressor 1 Rats Recombinant Proteins - metabolism Repressor Proteins - metabolism Saccharomyces cerevisiae Proteins Sequence Alignment Transcription Factors - metabolism Transcription. Transcription factor. Splicing. Rna processing Yeasts |
title | Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin |
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