BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells
We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 in...
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| creator | Kim, Nam-Hee Yoshimaru, Tetsuro Chen, Yi-An Matsuo, Taisuke Komatsu, Masato Miyoshi, Yasuo Tanaka, Eiji Sasa, Mitsunori Mizuguchi, Kenji Katagiri, Toyomasa |
| description | We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERα). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERα signals in breast cancer cells. |
| doi_str_mv | 10.1371/journal.pone.0127707 |
| format | Article |
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However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERα). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERα signals in breast cancer cells.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0127707</identifier><identifier>PMID: 26052702</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha Karyopherins - metabolism ; Amino acids ; Animals ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Brefeldin A ; Cancer ; Cell cycle ; Cell Line, Tumor ; Cell Nucleus - drug effects ; Cell Nucleus - metabolism ; Cercopithecus aethiops ; COS Cells ; Cytoplasm ; Estrogen Receptor alpha - metabolism ; Estrogens ; Estrogens - pharmacology ; Female ; Fibroblasts ; Genomes ; Guanine ; Guanine nucleotide exchange factor ; Guanine Nucleotide Exchange Factors - metabolism ; Humans ; Imports ; Inhibition ; Kinases ; Localization ; Medicine ; Models, Biological ; Morphology ; Mycoplasma ; Nuclear transport ; Nuclei (cytology) ; Orthodontics ; Orthopedics ; Prohibitin ; Protein Binding - drug effects ; Protein Transport - drug effects ; Proteins ; Repressor Proteins - metabolism ; siRNA ; Surgery ; Transcriptional Activation - drug effects ; Translocation ; Tumor suppressor genes</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0127707</ispartof><rights>2015 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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 Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Kim et al 2015 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-46d4d19d80f1e071a667f0e02632136029dfedaa9d90f880a071f017799032253</citedby><cites>FETCH-LOGICAL-c592t-46d4d19d80f1e071a667f0e02632136029dfedaa9d90f880a071f017799032253</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460025/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460025/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26052702$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Nam-Hee</creatorcontrib><creatorcontrib>Yoshimaru, Tetsuro</creatorcontrib><creatorcontrib>Chen, Yi-An</creatorcontrib><creatorcontrib>Matsuo, Taisuke</creatorcontrib><creatorcontrib>Komatsu, Masato</creatorcontrib><creatorcontrib>Miyoshi, Yasuo</creatorcontrib><creatorcontrib>Tanaka, Eiji</creatorcontrib><creatorcontrib>Sasa, Mitsunori</creatorcontrib><creatorcontrib>Mizuguchi, Kenji</creatorcontrib><creatorcontrib>Katagiri, Toyomasa</creatorcontrib><title>BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERα). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERα signals in breast cancer cells.</description><subject>alpha Karyopherins - metabolism</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Brefeldin A</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>Cytoplasm</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Estrogens</subject><subject>Estrogens - pharmacology</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Genomes</subject><subject>Guanine</subject><subject>Guanine nucleotide exchange factor</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Humans</subject><subject>Imports</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Localization</subject><subject>Medicine</subject><subject>Models, Biological</subject><subject>Morphology</subject><subject>Mycoplasma</subject><subject>Nuclear transport</subject><subject>Nuclei (cytology)</subject><subject>Orthodontics</subject><subject>Orthopedics</subject><subject>Prohibitin</subject><subject>Protein Binding - drug effects</subject><subject>Protein Transport - drug effects</subject><subject>Proteins</subject><subject>Repressor Proteins - metabolism</subject><subject>siRNA</subject><subject>Surgery</subject><subject>Transcriptional Activation - drug effects</subject><subject>Translocation</subject><subject>Tumor suppressor genes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uk1v1DAUjBCIfsA_QGCJc5bnjzjxBam7lHZFgR7K2fIm9sYr105tpxJH_nnTblq1B062_GbmjUdTFB8wLDCt8ZddGKNXbjEErxeASV1D_ao4xIKSkhOgr5_dD4qjlHYAFW04f1scEA4VqYEcFv-W6zOK1r63G5sTyr1GpynHsNW-_KYH7TvtM_o1tk6riK6i8smFVmUbPAoGXZ4vCbq1Cv0cXbaD0-iHin_D0OtofXnihl6hyxiytj4h69EyapUyWinf6ohW2rn0rnhjlEv6_XweF3--n16tzsuL32fr1clF2VaC5JLxjnVYdA0YrKHGivPagAbCKcGUAxGd0Z1SohNgmgbUhDGA61oIoIRU9Lj4tNcdXEhyTi9JzBteN5gyNiHWe0QX1E4O0V5Pf5FBWfnwEOJWqpjtFIVkDWZcmImnKoZhIwQ3oFrWsQ2HlvJJ6-u8bdxc666dUozKvRB9OfG2l9twKxnjAA92P88CMdyMOuX_WGZ7VBtDSlGbpw0Y5H1NHlnyviZyrslE-_jc3RPpsRf0DuL1uoo</recordid><startdate>20150608</startdate><enddate>20150608</enddate><creator>Kim, Nam-Hee</creator><creator>Yoshimaru, Tetsuro</creator><creator>Chen, Yi-An</creator><creator>Matsuo, Taisuke</creator><creator>Komatsu, Masato</creator><creator>Miyoshi, Yasuo</creator><creator>Tanaka, Eiji</creator><creator>Sasa, Mitsunori</creator><creator>Mizuguchi, Kenji</creator><creator>Katagiri, Toyomasa</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>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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150608</creationdate><title>BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells</title><author>Kim, Nam-Hee ; Yoshimaru, Tetsuro ; Chen, Yi-An ; Matsuo, Taisuke ; Komatsu, Masato ; Miyoshi, Yasuo ; Tanaka, Eiji ; Sasa, Mitsunori ; Mizuguchi, Kenji ; Katagiri, Toyomasa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-46d4d19d80f1e071a667f0e02632136029dfedaa9d90f880a071f017799032253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>alpha Karyopherins - metabolism</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Brefeldin A</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>Cytoplasm</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Estrogens</topic><topic>Estrogens - pharmacology</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Genomes</topic><topic>Guanine</topic><topic>Guanine nucleotide exchange factor</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Humans</topic><topic>Imports</topic><topic>Inhibition</topic><topic>Kinases</topic><topic>Localization</topic><topic>Medicine</topic><topic>Models, Biological</topic><topic>Morphology</topic><topic>Mycoplasma</topic><topic>Nuclear transport</topic><topic>Nuclei (cytology)</topic><topic>Orthodontics</topic><topic>Orthopedics</topic><topic>Prohibitin</topic><topic>Protein Binding - 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However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2-dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERα). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERα signals in breast cancer cells.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26052702</pmid><doi>10.1371/journal.pone.0127707</doi><oa>free_for_read</oa></addata></record> |
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| subjects | alpha Karyopherins - metabolism Amino acids Animals Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Brefeldin A Cancer Cell cycle Cell Line, Tumor Cell Nucleus - drug effects Cell Nucleus - metabolism Cercopithecus aethiops COS Cells Cytoplasm Estrogen Receptor alpha - metabolism Estrogens Estrogens - pharmacology Female Fibroblasts Genomes Guanine Guanine nucleotide exchange factor Guanine Nucleotide Exchange Factors - metabolism Humans Imports Inhibition Kinases Localization Medicine Models, Biological Morphology Mycoplasma Nuclear transport Nuclei (cytology) Orthodontics Orthopedics Prohibitin Protein Binding - drug effects Protein Transport - drug effects Proteins Repressor Proteins - metabolism siRNA Surgery Transcriptional Activation - drug effects Translocation Tumor suppressor genes |
| title | BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T12%3A17%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=BIG3%20Inhibits%20the%20Estrogen-Dependent%20Nuclear%20Translocation%20of%20PHB2%20via%20Multiple%20Karyopherin-Alpha%20Proteins%20in%20Breast%20Cancer%20Cells&rft.jtitle=PloS%20one&rft.au=Kim,%20Nam-Hee&rft.date=2015-06-08&rft.volume=10&rft.issue=6&rft.spage=e0127707&rft.pages=e0127707-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0127707&rft_dat=%3Cproquest_plos_%3E3708538031%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1686781344&rft_id=info:pmid/26052702&rft_doaj_id=oai_doaj_org_article_481469f813a5410b996f0ac4d4b60c36&rfr_iscdi=true |