Ligand-Dependent Activation of Transcription in vitro by Retinoic Acid Receptor α /retinoid X Receptor α Heterodimers That Mimics Transactivation by Retinoids in vivo
All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.1995-2000 |
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creator | Dilworth, F. Jeffrey Fromental-Ramain, Catherine Remboutsika, Eumorphia Benecke, Arndt Chambon, Pierre |
description | All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an in vitro transcription system using a chromatin template made up of a minimal promoter and a direct repeat with 5-spacing-based RA response element. RARα and RXRα were expressed in and purified from baculovirus-infected Sf9 cells, and transcription was carried out by using naked DNA or chromatin templates. Transcription from naked templates was not affected by the presence of RA and/or RAR/RXR heterodimers. In contrast, very little transcription occurred from chromatin templates in the absence of RA or RAR/RXR heterodimers whereas their addition resulted in a dosage-dependent stimulation of transcription that never exceeded that occurring on naked DNA templates. Most importantly, the addition of synthetic agonistic or antagonistic retinoids to the chromatin transcription system mimicked their stimulatory or inhibitory action in vivo, and activation by a RXR-specific retinoid was subordinated to the binding of an agonist ligand to the RAR partner. Moreover, the addition of the p300 coactivator generated a synergistic enhancement of transcription. Thus, the dissection of this transcription system ultimately should lead to the elucidation of the molecular mechanisms by which RAR/RXR heterodimers control transcription in a ligand-dependent manner. |
doi_str_mv | 10.1073/pnas.96.5.1995 |
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Jeffrey ; Fromental-Ramain, Catherine ; Remboutsika, Eumorphia ; Benecke, Arndt ; Chambon, Pierre</creator><creatorcontrib>Dilworth, F. Jeffrey ; Fromental-Ramain, Catherine ; Remboutsika, Eumorphia ; Benecke, Arndt ; Chambon, Pierre</creatorcontrib><description>All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an in vitro transcription system using a chromatin template made up of a minimal promoter and a direct repeat with 5-spacing-based RA response element. RARα and RXRα were expressed in and purified from baculovirus-infected Sf9 cells, and transcription was carried out by using naked DNA or chromatin templates. Transcription from naked templates was not affected by the presence of RA and/or RAR/RXR heterodimers. In contrast, very little transcription occurred from chromatin templates in the absence of RA or RAR/RXR heterodimers whereas their addition resulted in a dosage-dependent stimulation of transcription that never exceeded that occurring on naked DNA templates. Most importantly, the addition of synthetic agonistic or antagonistic retinoids to the chromatin transcription system mimicked their stimulatory or inhibitory action in vivo, and activation by a RXR-specific retinoid was subordinated to the binding of an agonist ligand to the RAR partner. Moreover, the addition of the p300 coactivator generated a synergistic enhancement of transcription. Thus, the dissection of this transcription system ultimately should lead to the elucidation of the molecular mechanisms by which RAR/RXR heterodimers control transcription in a ligand-dependent manner.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.96.5.1995</identifier><identifier>PMID: 10051583</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Agonists ; Alitretinoin ; Animals ; Biochemistry ; Biological Sciences ; Cell Line ; Chromatin ; Chromatin - genetics ; Cloning, Molecular ; Dimerization ; DNA ; Genes ; Histones ; Ligands ; Mice ; Promoter Regions, Genetic ; Protein Multimerization ; Proteins ; Receptors ; Receptors, Retinoic Acid - chemistry ; Receptors, Retinoic Acid - genetics ; Receptors, Retinoic Acid - metabolism ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Retinoic Acid Receptor alpha ; Retinoid X Receptors ; Retinoids ; Spodoptera ; Templates, Genetic ; Transactivation ; Transcription Factors - chemistry ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic - drug effects ; Transcriptional activation ; Transcriptional Activation - drug effects ; Transfection ; Tretinoin - pharmacology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (5), p.1995-2000</ispartof><rights>Copyright 1993-1999 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 2, 1999</rights><rights>Copyright © 1999, The National Academy of Sciences 1999</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c514t-da6a0fb297f07cafa878a0ff0e0c7fa4b756d934cf13e93f239d638cd21844dc3</citedby><cites>FETCH-LOGICAL-c514t-da6a0fb297f07cafa878a0ff0e0c7fa4b756d934cf13e93f239d638cd21844dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/96/5.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/47002$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/47002$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10051583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dilworth, F. Jeffrey</creatorcontrib><creatorcontrib>Fromental-Ramain, Catherine</creatorcontrib><creatorcontrib>Remboutsika, Eumorphia</creatorcontrib><creatorcontrib>Benecke, Arndt</creatorcontrib><creatorcontrib>Chambon, Pierre</creatorcontrib><title>Ligand-Dependent Activation of Transcription in vitro by Retinoic Acid Receptor α /retinoid X Receptor α Heterodimers That Mimics Transactivation by Retinoids in vivo</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an in vitro transcription system using a chromatin template made up of a minimal promoter and a direct repeat with 5-spacing-based RA response element. RARα and RXRα were expressed in and purified from baculovirus-infected Sf9 cells, and transcription was carried out by using naked DNA or chromatin templates. Transcription from naked templates was not affected by the presence of RA and/or RAR/RXR heterodimers. In contrast, very little transcription occurred from chromatin templates in the absence of RA or RAR/RXR heterodimers whereas their addition resulted in a dosage-dependent stimulation of transcription that never exceeded that occurring on naked DNA templates. Most importantly, the addition of synthetic agonistic or antagonistic retinoids to the chromatin transcription system mimicked their stimulatory or inhibitory action in vivo, and activation by a RXR-specific retinoid was subordinated to the binding of an agonist ligand to the RAR partner. Moreover, the addition of the p300 coactivator generated a synergistic enhancement of transcription. Thus, the dissection of this transcription system ultimately should lead to the elucidation of the molecular mechanisms by which RAR/RXR heterodimers control transcription in a ligand-dependent manner.</description><subject>Agonists</subject><subject>Alitretinoin</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Biological Sciences</subject><subject>Cell Line</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Cloning, Molecular</subject><subject>Dimerization</subject><subject>DNA</subject><subject>Genes</subject><subject>Histones</subject><subject>Ligands</subject><subject>Mice</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Multimerization</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Retinoic Acid - chemistry</subject><subject>Receptors, Retinoic Acid - genetics</subject><subject>Receptors, Retinoic Acid - metabolism</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Retinoic Acid Receptor alpha</subject><subject>Retinoid X Receptors</subject><subject>Retinoids</subject><subject>Spodoptera</subject><subject>Templates, Genetic</subject><subject>Transactivation</subject><subject>Transcription Factors - chemistry</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transcriptional activation</subject><subject>Transcriptional Activation - drug effects</subject><subject>Transfection</subject><subject>Tretinoin - pharmacology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks1u1DAUhSMEokNhywIJZLHoLqkdx3EssanKT5EGIaFBYmd5_NN6lLGD7YzoG7HlRXgmHDK0UxawsnzPd-71tU5RPEWwQpDi08GJWLG2IhVijNwrFggyVLYNg_eLBYQ1Lbumbo6KRzFuIISMdPBhcYQgJIh0eFF8X9pL4VT5Wg_aKe0SOJPJ7kSy3gFvwCoIF2Www--CdWBnU_BgfQ0-6WSdtzIbrMo3qYfkA_j5A5yGWVLgy536hU46eGW3OkSwuhIJfLBbK-M8RNzOve2u4jxz5x8XD4zoo36yP4-Lz2_frM4vyuXHd-_Pz5alJKhJpRKtgGZdM2oglcKIjna5YKCGkhrRrClpFcONNAhrhk2NmWpxJ1WNuqZREh8Xr-a-w7jeaiXzlwTR8yHYrQjX3AvL7yrOXvFLv-N1S2uS7Sd7e_BfRx0T39oodd8Lp_0YectaiDoM_wsiilpCEc3gy7_AjR-Dy3_Aa4hw3ppNUDVDMvgYgzY3D0aQT0HhU1A4aznhU1Cy4cXhmgf4nIwMPN8Dk_GPfNjg5F86N2PfJ_0tZfDZDG5izsEN2dCcTvwL0xHgKA</recordid><startdate>19990302</startdate><enddate>19990302</enddate><creator>Dilworth, F. 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Jeffrey</creatorcontrib><creatorcontrib>Fromental-Ramain, Catherine</creatorcontrib><creatorcontrib>Remboutsika, Eumorphia</creatorcontrib><creatorcontrib>Benecke, Arndt</creatorcontrib><creatorcontrib>Chambon, Pierre</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dilworth, F. Jeffrey</au><au>Fromental-Ramain, Catherine</au><au>Remboutsika, Eumorphia</au><au>Benecke, Arndt</au><au>Chambon, Pierre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ligand-Dependent Activation of Transcription in vitro by Retinoic Acid Receptor α /retinoid X Receptor α Heterodimers That Mimics Transactivation by Retinoids in vivo</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1999-03-02</date><risdate>1999</risdate><volume>96</volume><issue>5</issue><spage>1995</spage><epage>2000</epage><pages>1995-2000</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>All-trans and 9-cis retinoic acids (RA) signals are transduced by retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers that act as functional units controlling the transcription of RA-responsive genes. With the aim of elucidating the underlying molecular mechanisms, we have developed an in vitro transcription system using a chromatin template made up of a minimal promoter and a direct repeat with 5-spacing-based RA response element. RARα and RXRα were expressed in and purified from baculovirus-infected Sf9 cells, and transcription was carried out by using naked DNA or chromatin templates. Transcription from naked templates was not affected by the presence of RA and/or RAR/RXR heterodimers. In contrast, very little transcription occurred from chromatin templates in the absence of RA or RAR/RXR heterodimers whereas their addition resulted in a dosage-dependent stimulation of transcription that never exceeded that occurring on naked DNA templates. Most importantly, the addition of synthetic agonistic or antagonistic retinoids to the chromatin transcription system mimicked their stimulatory or inhibitory action in vivo, and activation by a RXR-specific retinoid was subordinated to the binding of an agonist ligand to the RAR partner. Moreover, the addition of the p300 coactivator generated a synergistic enhancement of transcription. Thus, the dissection of this transcription system ultimately should lead to the elucidation of the molecular mechanisms by which RAR/RXR heterodimers control transcription in a ligand-dependent manner.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10051583</pmid><doi>10.1073/pnas.96.5.1995</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Agonists Alitretinoin Animals Biochemistry Biological Sciences Cell Line Chromatin Chromatin - genetics Cloning, Molecular Dimerization DNA Genes Histones Ligands Mice Promoter Regions, Genetic Protein Multimerization Proteins Receptors Receptors, Retinoic Acid - chemistry Receptors, Retinoic Acid - genetics Receptors, Retinoic Acid - metabolism Recombinant Proteins - chemistry Recombinant Proteins - metabolism Retinoic Acid Receptor alpha Retinoid X Receptors Retinoids Spodoptera Templates, Genetic Transactivation Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic - drug effects Transcriptional activation Transcriptional Activation - drug effects Transfection Tretinoin - pharmacology |
title | Ligand-Dependent Activation of Transcription in vitro by Retinoic Acid Receptor α /retinoid X Receptor α Heterodimers That Mimics Transactivation by Retinoids in vivo |
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