Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP
The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a tran...
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| Veröffentlicht in: | PloS one 2011-09, Vol.6 (9), p.e24659-e24659 |
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| creator | Elvenes, Julianne Thomassen, Ernst Ivan Simon Johnsen, Sylvia Sagen Kaino, Katrine Sjøttem, Eva Johansen, Terje |
| description | The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer. |
| doi_str_mv | 10.1371/journal.pone.0024659 |
| format | Article |
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The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0024659</identifier><identifier>PMID: 21935435</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Androgen receptors ; Androgens ; Basale medisinske, odontologiske og veterinærmedisinske fag: 710 ; Basic medical, dental and veterinary science disciplines: 710 ; Binding ; Biology ; Brain research ; Cancer ; Cell Line ; Cell Line, Tumor ; Cell Nucleus - metabolism ; Chromatin Immunoprecipitation ; Cytoplasm ; Deoxyribonucleic acid ; DNA ; Drugs ; Etiology ; Eye Proteins - genetics ; Eye Proteins - metabolism ; Fluorescence Resonance Energy Transfer ; Gene expression ; HeLa Cells ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Inhibition ; Ligands ; Medical disciplines: 700 ; Medical genetics: 714 ; Medical research ; Medisinsk genetikk: 714 ; Medisinske Fag: 700 ; Microscopy, Confocal ; Paired Box Transcription Factors - genetics ; Paired Box Transcription Factors - metabolism ; Pax6 protein ; PAX6 Transcription Factor ; Physiology ; Plasmids ; Promoter Regions, Genetic - genetics ; Prostate cancer ; Protein Binding ; Proteins ; Real-Time Polymerase Chain Reaction ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Recruitment ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Reproductive system ; Reproductive systems ; Rodents ; Stem cells ; Transcription factors ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Traumatic brain injury ; VDP</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e24659-e24659</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Elvenes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.</description><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Basale medisinske, odontologiske og veterinærmedisinske fag: 710</subject><subject>Basic medical, dental and veterinary science disciplines: 710</subject><subject>Binding</subject><subject>Biology</subject><subject>Brain research</subject><subject>Cancer</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - metabolism</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cytoplasm</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drugs</subject><subject>Etiology</subject><subject>Eye Proteins - genetics</subject><subject>Eye Proteins - metabolism</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>Gene expression</subject><subject>HeLa Cells</subject><subject>Homeodomain Proteins - 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genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Reproductive system</subject><subject>Reproductive systems</subject><subject>Rodents</subject><subject>Stem cells</subject><subject>Transcription factors</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Traumatic brain injury</subject><subject>VDP</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>3HK</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01v1DAQhiMEomXhHyCIhATisIsdO3Z8QSoVHytV6opWXC3Hmey6ZO3Fdqr23-Ow2dKgHlAOjsbPvPa848mylxgtMOH4w5XrvVXdYucsLBAqKCvFo-wYC1LMWYHI43v_R9mzEK4QKknF2NPsqEg7JSXlcfZzpW5Y7mHnIQQIubKNd2uwKaRhF52fb6ExKkKTR69sUDqaaxWNs3l9mxu7MbWJxq4H3vcmbsHG3LV53ECu3Ug7n1-sPq2eZ09a1QV4Ma6z7PLL58vTb_Oz86_L05OzueaYxnnNGKkb3bRFSZAoS4IJAK2pqgXSWKgWM1GUtGRQiRSsq7bhRVtwJhAFUpFZ9novu-tckKNNQWKCKoEY5iIRyz3ROHUld95slb-VThn5J-D8Wiofje5Acl03VYVZLVpGeaGTb5yUbUMJZ5rSQevjeFpfJ6t0qt-rbiI63bFmI9fuWhLMKebDdV_tBbQ3IVkprfNKYoQIlxSlLs2yd-MJ3v3qIUS5NUFD1ykLrg-yEoQXiIpB6s0_5MPVj9RapQKNbV26lx405QnlrOJCsCJRiweo9DWwNTq9udak-CTh_SQhMRFu4lr1Icjlxff_Z89_TNm399gNqC5uguv64Q2GKUgPRroQPLR3TcBIDiNzcEMOIyPHkfnr_75Nd0mHGSG_AW8gEIU</recordid><startdate>20110915</startdate><enddate>20110915</enddate><creator>Elvenes, Julianne</creator><creator>Thomassen, Ernst Ivan Simon</creator><creator>Johnsen, Sylvia Sagen</creator><creator>Kaino, Katrine</creator><creator>Sjøttem, Eva</creator><creator>Johansen, Terje</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>3HK</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110915</creationdate><title>Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP</title><author>Elvenes, Julianne ; Thomassen, Ernst Ivan Simon ; Johnsen, Sylvia Sagen ; Kaino, Katrine ; Sjøttem, Eva ; Johansen, Terje</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c714t-b663bdcdf2530955313ee4b4ab90c19af16925456e894abb8fd72f276904e383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Androgen receptors</topic><topic>Androgens</topic><topic>Basale medisinske, odontologiske og veterinærmedisinske fag: 710</topic><topic>Basic medical, dental and veterinary science disciplines: 710</topic><topic>Binding</topic><topic>Biology</topic><topic>Brain research</topic><topic>Cancer</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Nucleus - metabolism</topic><topic>Chromatin Immunoprecipitation</topic><topic>Cytoplasm</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drugs</topic><topic>Etiology</topic><topic>Eye Proteins - genetics</topic><topic>Eye Proteins - metabolism</topic><topic>Fluorescence Resonance Energy Transfer</topic><topic>Gene expression</topic><topic>HeLa Cells</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>Inhibition</topic><topic>Ligands</topic><topic>Medical disciplines: 700</topic><topic>Medical genetics: 714</topic><topic>Medical research</topic><topic>Medisinsk genetikk: 714</topic><topic>Medisinske Fag: 700</topic><topic>Microscopy, Confocal</topic><topic>Paired Box Transcription Factors - genetics</topic><topic>Paired Box Transcription Factors - metabolism</topic><topic>Pax6 protein</topic><topic>PAX6 Transcription Factor</topic><topic>Physiology</topic><topic>Plasmids</topic><topic>Promoter Regions, Genetic - 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The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21935435</pmid><doi>10.1371/journal.pone.0024659</doi><tpages>e24659</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Androgen receptors Androgens Basale medisinske, odontologiske og veterinærmedisinske fag: 710 Basic medical, dental and veterinary science disciplines: 710 Binding Biology Brain research Cancer Cell Line Cell Line, Tumor Cell Nucleus - metabolism Chromatin Immunoprecipitation Cytoplasm Deoxyribonucleic acid DNA Drugs Etiology Eye Proteins - genetics Eye Proteins - metabolism Fluorescence Resonance Energy Transfer Gene expression HeLa Cells Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Immunoblotting Immunoprecipitation Inhibition Ligands Medical disciplines: 700 Medical genetics: 714 Medical research Medisinsk genetikk: 714 Medisinske Fag: 700 Microscopy, Confocal Paired Box Transcription Factors - genetics Paired Box Transcription Factors - metabolism Pax6 protein PAX6 Transcription Factor Physiology Plasmids Promoter Regions, Genetic - genetics Prostate cancer Protein Binding Proteins Real-Time Polymerase Chain Reaction Receptors, Androgen - genetics Receptors, Androgen - metabolism Recruitment Repressor Proteins - genetics Repressor Proteins - metabolism Reproductive system Reproductive systems Rodents Stem cells Transcription factors Transcription Factors - genetics Transcription Factors - metabolism Traumatic brain injury VDP |
| title | Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T02%3A24%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pax6%20represses%20androgen%20receptor-mediated%20transactivation%20by%20inhibiting%20recruitment%20of%20the%20coactivator%20SPBP&rft.jtitle=PloS%20one&rft.au=Elvenes,%20Julianne&rft.date=2011-09-15&rft.volume=6&rft.issue=9&rft.spage=e24659&rft.epage=e24659&rft.pages=e24659-e24659&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0024659&rft_dat=%3Cgale_plos_%3EA476879962%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308906179&rft_id=info:pmid/21935435&rft_galeid=A476879962&rft_doaj_id=oai_doaj_org_article_7cbd8816b9f6472c935735fd4376c449&rfr_iscdi=true |