Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ
We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cell...
Gespeichert in:
| Veröffentlicht in: | Oncogene 2009-03, Vol.28 (12), p.1561-1568 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1568 |
|---|---|
| container_issue | 12 |
| container_start_page | 1561 |
| container_title | Oncogene |
| container_volume | 28 |
| creator | Gustafson, T L Wellberg, E Laffin, B Schilling, L Metz, R P Zahnow, C A Porter, W W |
| description | We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-
Ras
(Ha-
Ras
) induces CCAAT/enhance binding protein β (C/EBPβ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpβ-dependent inhibition of SIM2s,
C
/ebpβ
−/−
mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpβ isoforms decreased SIM2s mRNA levels in C/ebpβ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-
Ras
-transformed breast epithelial cells and identify SIM2s as a target of C/EBPβ and NOTCH signaling. |
| doi_str_mv | 10.1038/onc.2008.497 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2692552</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A197106251</galeid><sourcerecordid>A197106251</sourcerecordid><originalsourceid>FETCH-LOGICAL-c491t-aaf941fe2a0c7ff5a5643d66e7781490be71689933d42caa41121c0442edcb6a3</originalsourceid><addsrcrecordid>eNptkd1uEzEQhS0EoqFwxwOshLhjU4_XP-sbpBC1FKlQxM-15XjtjauNHewEidfiQXgmpkrUqlLlC0sz3xydmUPIa6BzoF1_lpObM0r7OdfqCZkBV7IVQvOnZEa1oK1mHTshL2q9oZQqTdlzcgIapGZKzki4tO03W5tdsamGXDZ2F3Nqcmg-Ly-ALhrnp6k2k7cDQrkpflt8rUfme0zj5DcxDX5oGQLrkvfjuvly_WN52dg0NMuz8w9f__19SZ4FO1X_6vifkp8X58i0V9cfPy0XV63jGnattUFzCJ5Z6lQIwgrJu0FKr1QPXNOVVyB7rbtu4MxZywEYOMo584NbSdudkvcH3e1-tcGaT7jYZLYlbmz5Y7KN5mEnxbUZ82_D8B5CMBR4cxQo-dfe1525yfuS0DMiHLpe9LK7p0Y7eRNTyCjmNrE6swCtgEomAKn5IxS-AU_mcvIhYv3BwLvDgCu51uLDnXGg5jZsg2Gb27ANho3426NXW52dAkboYr2bYdCpXkCPXHvgKrbS6Mv9To_q_gfsfrVq</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2641385863</pqid></control><display><type>article</type><title>Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ</title><source>Springer Nature - Complete Springer Journals</source><source>Nature Journals Online</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Gustafson, T L ; Wellberg, E ; Laffin, B ; Schilling, L ; Metz, R P ; Zahnow, C A ; Porter, W W</creator><creatorcontrib>Gustafson, T L ; Wellberg, E ; Laffin, B ; Schilling, L ; Metz, R P ; Zahnow, C A ; Porter, W W</creatorcontrib><description>We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-
Ras
(Ha-
Ras
) induces CCAAT/enhance binding protein β (C/EBPβ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpβ-dependent inhibition of SIM2s,
C
/ebpβ
−/−
mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpβ isoforms decreased SIM2s mRNA levels in C/ebpβ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-
Ras
-transformed breast epithelial cells and identify SIM2s as a target of C/EBPβ and NOTCH signaling.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2008.497</identifier><identifier>PMID: 19169276</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Biological and medical sciences ; Breast cancer ; Cell Biology ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular signal transduction ; DNA binding proteins ; Epithelial cells ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene silencing ; Genetic transformation ; Helix-loop-helix proteins (basic) ; Human Genetics ; Internal Medicine ; Isoforms ; Kinases ; Mammary gland ; Medicine ; Medicine & Public Health ; Molecular and cellular biology ; Oncology ; Physiological aspects ; Ras protein ; short-communication ; Signal transduction ; Transcription factors ; Tumor suppressor genes ; Tumors</subject><ispartof>Oncogene, 2009-03, Vol.28 (12), p.1561-1568</ispartof><rights>Macmillan Publishers Limited 2009</rights><rights>2009 INIST-CNRS</rights><rights>COPYRIGHT 2009 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2009.</rights><rights>2009 Macmillan Publishers Limited All rights reserved 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-aaf941fe2a0c7ff5a5643d66e7781490be71689933d42caa41121c0442edcb6a3</citedby><cites>FETCH-LOGICAL-c491t-aaf941fe2a0c7ff5a5643d66e7781490be71689933d42caa41121c0442edcb6a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2008.497$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2008.497$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21378518$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Gustafson, T L</creatorcontrib><creatorcontrib>Wellberg, E</creatorcontrib><creatorcontrib>Laffin, B</creatorcontrib><creatorcontrib>Schilling, L</creatorcontrib><creatorcontrib>Metz, R P</creatorcontrib><creatorcontrib>Zahnow, C A</creatorcontrib><creatorcontrib>Porter, W W</creatorcontrib><title>Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-
Ras
(Ha-
Ras
) induces CCAAT/enhance binding protein β (C/EBPβ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpβ-dependent inhibition of SIM2s,
C
/ebpβ
−/−
mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpβ isoforms decreased SIM2s mRNA levels in C/ebpβ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-
Ras
-transformed breast epithelial cells and identify SIM2s as a target of C/EBPβ and NOTCH signaling.</description><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Breast cancer</subject><subject>Cell Biology</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cellular signal transduction</subject><subject>DNA binding proteins</subject><subject>Epithelial cells</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Genetic transformation</subject><subject>Helix-loop-helix proteins (basic)</subject><subject>Human Genetics</subject><subject>Internal Medicine</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Mammary gland</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Molecular and cellular biology</subject><subject>Oncology</subject><subject>Physiological aspects</subject><subject>Ras protein</subject><subject>short-communication</subject><subject>Signal transduction</subject><subject>Transcription factors</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkd1uEzEQhS0EoqFwxwOshLhjU4_XP-sbpBC1FKlQxM-15XjtjauNHewEidfiQXgmpkrUqlLlC0sz3xydmUPIa6BzoF1_lpObM0r7OdfqCZkBV7IVQvOnZEa1oK1mHTshL2q9oZQqTdlzcgIapGZKzki4tO03W5tdsamGXDZ2F3Nqcmg-Ly-ALhrnp6k2k7cDQrkpflt8rUfme0zj5DcxDX5oGQLrkvfjuvly_WN52dg0NMuz8w9f__19SZ4FO1X_6vifkp8X58i0V9cfPy0XV63jGnattUFzCJ5Z6lQIwgrJu0FKr1QPXNOVVyB7rbtu4MxZywEYOMo584NbSdudkvcH3e1-tcGaT7jYZLYlbmz5Y7KN5mEnxbUZ82_D8B5CMBR4cxQo-dfe1525yfuS0DMiHLpe9LK7p0Y7eRNTyCjmNrE6swCtgEomAKn5IxS-AU_mcvIhYv3BwLvDgCu51uLDnXGg5jZsg2Gb27ANho3426NXW52dAkboYr2bYdCpXkCPXHvgKrbS6Mv9To_q_gfsfrVq</recordid><startdate>20090326</startdate><enddate>20090326</enddate><creator>Gustafson, T L</creator><creator>Wellberg, E</creator><creator>Laffin, B</creator><creator>Schilling, L</creator><creator>Metz, R P</creator><creator>Zahnow, C A</creator><creator>Porter, W W</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20090326</creationdate><title>Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ</title><author>Gustafson, T L ; Wellberg, E ; Laffin, B ; Schilling, L ; Metz, R P ; Zahnow, C A ; Porter, W W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-aaf941fe2a0c7ff5a5643d66e7781490be71689933d42caa41121c0442edcb6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Breast cancer</topic><topic>Cell Biology</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cellular signal transduction</topic><topic>DNA binding proteins</topic><topic>Epithelial cells</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Gene silencing</topic><topic>Genetic transformation</topic><topic>Helix-loop-helix proteins (basic)</topic><topic>Human Genetics</topic><topic>Internal Medicine</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Mammary gland</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Molecular and cellular biology</topic><topic>Oncology</topic><topic>Physiological aspects</topic><topic>Ras protein</topic><topic>short-communication</topic><topic>Signal transduction</topic><topic>Transcription factors</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gustafson, T L</creatorcontrib><creatorcontrib>Wellberg, E</creatorcontrib><creatorcontrib>Laffin, B</creatorcontrib><creatorcontrib>Schilling, L</creatorcontrib><creatorcontrib>Metz, R P</creatorcontrib><creatorcontrib>Zahnow, C A</creatorcontrib><creatorcontrib>Porter, W W</creatorcontrib><collection>Pascal-Francis</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gustafson, T L</au><au>Wellberg, E</au><au>Laffin, B</au><au>Schilling, L</au><au>Metz, R P</au><au>Zahnow, C A</au><au>Porter, W W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><date>2009-03-26</date><risdate>2009</risdate><volume>28</volume><issue>12</issue><spage>1561</spage><epage>1568</epage><pages>1561-1568</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-
Ras
(Ha-
Ras
) induces CCAAT/enhance binding protein β (C/EBPβ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpβ-dependent inhibition of SIM2s,
C
/ebpβ
−/−
mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpβ isoforms decreased SIM2s mRNA levels in C/ebpβ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-
Ras
-transformed breast epithelial cells and identify SIM2s as a target of C/EBPβ and NOTCH signaling.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19169276</pmid><doi>10.1038/onc.2008.497</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2009-03, Vol.28 (12), p.1561-1568 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2692552 |
| source | Springer Nature - Complete Springer Journals; Nature Journals Online; EZB-FREE-00999 freely available EZB journals |
| subjects | Apoptosis Biological and medical sciences Breast cancer Cell Biology Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular signal transduction DNA binding proteins Epithelial cells Fundamental and applied biological sciences. Psychology Gene expression Gene silencing Genetic transformation Helix-loop-helix proteins (basic) Human Genetics Internal Medicine Isoforms Kinases Mammary gland Medicine Medicine & Public Health Molecular and cellular biology Oncology Physiological aspects Ras protein short-communication Signal transduction Transcription factors Tumor suppressor genes Tumors |
| title | Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPβ |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T16%3A51%3A18IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Ha-Ras%20transformation%20of%20MCF10A%20cells%20leads%20to%20repression%20of%20Singleminded-2s%20through%20NOTCH%20and%20C/EBP%CE%B2&rft.jtitle=Oncogene&rft.au=Gustafson,%20T%20L&rft.date=2009-03-26&rft.volume=28&rft.issue=12&rft.spage=1561&rft.epage=1568&rft.pages=1561-1568&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/onc.2008.497&rft_dat=%3Cgale_pubme%3EA197106251%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2641385863&rft_id=info:pmid/19169276&rft_galeid=A197106251&rfr_iscdi=true |