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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (5), p.1995-2000
Hauptverfasser: Dilworth, F. Jeffrey, Fromental-Ramain, Catherine, Remboutsika, Eumorphia, Benecke, Arndt, Chambon, Pierre
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2000
container_issue 5
container_start_page 1995
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 96
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
format Article
fullrecord <record><control><sourceid>jstor_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_26725</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><jstor_id>47002</jstor_id><sourcerecordid>47002</sourcerecordid><originalsourceid>FETCH-LOGICAL-c514t-da6a0fb297f07cafa878a0ff0e0c7fa4b756d934cf13e93f239d638cd21844dc3</originalsourceid><addsrcrecordid>eNqFks1u1DAUhSMEokNhywIJZLHoLqkdx3EssanKT5EGIaFBYmd5_NN6lLGD7YzoG7HlRXgmHDK0UxawsnzPd-71tU5RPEWwQpDi08GJWLG2IhVijNwrFggyVLYNg_eLBYQ1Lbumbo6KRzFuIISMdPBhcYQgJIh0eFF8X9pL4VT5Wg_aKe0SOJPJ7kSy3gFvwCoIF2Www--CdWBnU_BgfQ0-6WSdtzIbrMo3qYfkA_j5A5yGWVLgy536hU46eGW3OkSwuhIJfLBbK-M8RNzOve2u4jxz5x8XD4zoo36yP4-Lz2_frM4vyuXHd-_Pz5alJKhJpRKtgGZdM2oglcKIjna5YKCGkhrRrClpFcONNAhrhk2NmWpxJ1WNuqZREh8Xr-a-w7jeaiXzlwTR8yHYrQjX3AvL7yrOXvFLv-N1S2uS7Sd7e_BfRx0T39oodd8Lp_0YectaiDoM_wsiilpCEc3gy7_AjR-Dy3_Aa4hw3ppNUDVDMvgYgzY3D0aQT0HhU1A4aznhU1Cy4cXhmgf4nIwMPN8Dk_GPfNjg5F86N2PfJ_0tZfDZDG5izsEN2dCcTvwL0xHgKA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>201351497</pqid></control><display><type>article</type><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><source>Jstor Complete Legacy</source><source>MEDLINE</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Dilworth, F. 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. Jeffrey</creator><creator>Fromental-Ramain, Catherine</creator><creator>Remboutsika, Eumorphia</creator><creator>Benecke, Arndt</creator><creator>Chambon, Pierre</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19990302</creationdate><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><author>Dilworth, F. Jeffrey ; Fromental-Ramain, Catherine ; Remboutsika, Eumorphia ; Benecke, Arndt ; Chambon, Pierre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-da6a0fb297f07cafa878a0ff0e0c7fa4b756d934cf13e93f239d638cd21844dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Agonists</topic><topic>Alitretinoin</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Biological Sciences</topic><topic>Cell Line</topic><topic>Chromatin</topic><topic>Chromatin - genetics</topic><topic>Cloning, Molecular</topic><topic>Dimerization</topic><topic>DNA</topic><topic>Genes</topic><topic>Histones</topic><topic>Ligands</topic><topic>Mice</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Multimerization</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Receptors, Retinoic Acid - chemistry</topic><topic>Receptors, Retinoic Acid - genetics</topic><topic>Receptors, Retinoic Acid - metabolism</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>Retinoic Acid Receptor alpha</topic><topic>Retinoid X Receptors</topic><topic>Retinoids</topic><topic>Spodoptera</topic><topic>Templates, Genetic</topic><topic>Transactivation</topic><topic>Transcription Factors - chemistry</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transcriptional activation</topic><topic>Transcriptional Activation - drug effects</topic><topic>Transfection</topic><topic>Tretinoin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dilworth, F. 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 &amp; 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>
fulltext fulltext
identifier ISSN: 0027-8424
ispartof Proceedings of the National Academy of Sciences - PNAS, 1999-03, Vol.96 (5), p.1995-2000
issn 0027-8424
1091-6490
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_26725
source Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T01%3A30%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ligand-Dependent%20Activation%20of%20Transcription%20in%20vitro%20by%20Retinoic%20Acid%20Receptor%20%CE%B1%20/retinoid%20X%20Receptor%20%CE%B1%20Heterodimers%20That%20Mimics%20Transactivation%20by%20Retinoids%20in%20vivo&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Dilworth,%20F.%20Jeffrey&rft.date=1999-03-02&rft.volume=96&rft.issue=5&rft.spage=1995&rft.epage=2000&rft.pages=1995-2000&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.96.5.1995&rft_dat=%3Cjstor_pubme%3E47002%3C/jstor_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=201351497&rft_id=info:pmid/10051583&rft_jstor_id=47002&rfr_iscdi=true