Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells
Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey distinct cellular responses. Therefore, we have in...
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| Veröffentlicht in: | Molecular cancer research 2009-08, Vol.7 (8), p.1342-1353 |
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| creator | Dzwonek, Joanna Preobrazhenska, Olena Cazzola, Silvia Conidi, Andrea Schellens, Ann van Dinther, Maarten Stubbs, Andrew Klippel, Anke Huylebroeck, Danny ten Dijke, Peter Verschueren, Kristin |
| description | Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical
properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey
distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic
and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently
depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation
of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed,
including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases,
and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown
on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated
events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342–53) |
| doi_str_mv | 10.1158/1541-7786.MCR-08-0558 |
| format | Article |
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properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey
distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic
and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently
depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation
of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed,
including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases,
and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown
on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated
events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342–53)</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-08-0558</identifier><identifier>PMID: 19671686</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; apoptosis ; Apoptosis - drug effects ; breast cancer ; cell proliferation ; Cell Shape - drug effects ; Cytoskeleton - drug effects ; Cytoskeleton - metabolism ; EMT ; Enzyme Induction - drug effects ; Epithelial Cells - drug effects ; Epithelial Cells - enzymology ; Epithelial Cells - metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation - drug effects ; Gene Knockdown Techniques ; GeneBloc ; Humans ; Intercellular Junctions - drug effects ; Intercellular Junctions - metabolism ; knockdown ; Mammary Glands, Animal - cytology ; Matrix Metalloproteinases - biosynthesis ; Mice ; Oligonucleotides, Antisense - pharmacology ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; siRNA ; Smad2 Protein - genetics ; Smad2 Protein - metabolism ; Smad3 Protein - genetics ; Smad3 Protein - metabolism ; Transforming Growth Factor beta - metabolism</subject><ispartof>Molecular cancer research, 2009-08, Vol.7 (8), p.1342-1353</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-f6eeb8b1d5310e03eb6bfbb0846750527aa5b45f60e91d4849dc87ef6d1c46533</citedby><cites>FETCH-LOGICAL-c387t-f6eeb8b1d5310e03eb6bfbb0846750527aa5b45f60e91d4849dc87ef6d1c46533</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19671686$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dzwonek, Joanna</creatorcontrib><creatorcontrib>Preobrazhenska, Olena</creatorcontrib><creatorcontrib>Cazzola, Silvia</creatorcontrib><creatorcontrib>Conidi, Andrea</creatorcontrib><creatorcontrib>Schellens, Ann</creatorcontrib><creatorcontrib>van Dinther, Maarten</creatorcontrib><creatorcontrib>Stubbs, Andrew</creatorcontrib><creatorcontrib>Klippel, Anke</creatorcontrib><creatorcontrib>Huylebroeck, Danny</creatorcontrib><creatorcontrib>ten Dijke, Peter</creatorcontrib><creatorcontrib>Verschueren, Kristin</creatorcontrib><title>Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical
properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey
distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic
and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently
depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation
of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed,
including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases,
and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown
on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated
events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342–53)</description><subject>Animals</subject><subject>apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>breast cancer</subject><subject>cell proliferation</subject><subject>Cell Shape - drug effects</subject><subject>Cytoskeleton - drug effects</subject><subject>Cytoskeleton - metabolism</subject><subject>EMT</subject><subject>Enzyme Induction - drug effects</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - enzymology</subject><subject>Epithelial Cells - metabolism</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>GeneBloc</subject><subject>Humans</subject><subject>Intercellular Junctions - drug effects</subject><subject>Intercellular Junctions - metabolism</subject><subject>knockdown</subject><subject>Mammary Glands, Animal - cytology</subject><subject>Matrix Metalloproteinases - biosynthesis</subject><subject>Mice</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>siRNA</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - genetics</subject><subject>Smad3 Protein - metabolism</subject><subject>Transforming Growth Factor beta - metabolism</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkNtKxDAQhoMonh9ByZ1X1WRz3EtZPKGr4OE6pMl0G2nTNWkRX8sH8ZlsccGbmYH_n5mfD6ETSs4pFfqCCk4LpbQ8Xy6eC6ILIoTeQvtUCFUwOhPb07zx7KGDnN8JmRGq5C7ao3OpqNRyHw0vrfUM32Vs8T184ccuJvBD9Db2eAk-2L5LuKvwa7IxV11qQ1zhm9R99jW-tm5Sf77xS1hF20xSiPixBbzshjxW27Y2feGrdehraIJt8AKaJh-hnco2GY43_RC9XV-9Lm6Lh6ebu8XlQ-GYVn1RSYBSl9QLRgkQBqUsq7IkmksliJgpa0XJRSUJzKnnms-90woq6anjUjB2iM7-7q5T9zFA7k0bshsT2AhjQKMYmysiOR-d4s_pUpdzgsqsU5iyG0rMBNxMMM0E04zADdFmAj7unW4-DGUL_n9rQ_g_Qh1W9WdIYJyNDlKCDDa52igz3mZ8xn4B_OOLGA</recordid><startdate>20090801</startdate><enddate>20090801</enddate><creator>Dzwonek, Joanna</creator><creator>Preobrazhenska, Olena</creator><creator>Cazzola, Silvia</creator><creator>Conidi, Andrea</creator><creator>Schellens, Ann</creator><creator>van Dinther, Maarten</creator><creator>Stubbs, Andrew</creator><creator>Klippel, Anke</creator><creator>Huylebroeck, Danny</creator><creator>ten Dijke, Peter</creator><creator>Verschueren, Kristin</creator><general>American Association for Cancer Research</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>7X8</scope></search><sort><creationdate>20090801</creationdate><title>Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells</title><author>Dzwonek, Joanna ; Preobrazhenska, Olena ; Cazzola, Silvia ; Conidi, Andrea ; Schellens, Ann ; van Dinther, Maarten ; Stubbs, Andrew ; Klippel, Anke ; Huylebroeck, Danny ; ten Dijke, Peter ; Verschueren, Kristin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-f6eeb8b1d5310e03eb6bfbb0846750527aa5b45f60e91d4849dc87ef6d1c46533</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>breast cancer</topic><topic>cell proliferation</topic><topic>Cell Shape - drug effects</topic><topic>Cytoskeleton - drug effects</topic><topic>Cytoskeleton - metabolism</topic><topic>EMT</topic><topic>Enzyme Induction - drug effects</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - enzymology</topic><topic>Epithelial Cells - metabolism</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Knockdown Techniques</topic><topic>GeneBloc</topic><topic>Humans</topic><topic>Intercellular Junctions - drug effects</topic><topic>Intercellular Junctions - metabolism</topic><topic>knockdown</topic><topic>Mammary Glands, Animal - cytology</topic><topic>Matrix Metalloproteinases - biosynthesis</topic><topic>Mice</topic><topic>Oligonucleotides, Antisense - pharmacology</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>siRNA</topic><topic>Smad2 Protein - genetics</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - genetics</topic><topic>Smad3 Protein - metabolism</topic><topic>Transforming Growth Factor beta - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dzwonek, Joanna</creatorcontrib><creatorcontrib>Preobrazhenska, Olena</creatorcontrib><creatorcontrib>Cazzola, Silvia</creatorcontrib><creatorcontrib>Conidi, Andrea</creatorcontrib><creatorcontrib>Schellens, Ann</creatorcontrib><creatorcontrib>van Dinther, Maarten</creatorcontrib><creatorcontrib>Stubbs, Andrew</creatorcontrib><creatorcontrib>Klippel, Anke</creatorcontrib><creatorcontrib>Huylebroeck, Danny</creatorcontrib><creatorcontrib>ten Dijke, Peter</creatorcontrib><creatorcontrib>Verschueren, Kristin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dzwonek, Joanna</au><au>Preobrazhenska, Olena</au><au>Cazzola, Silvia</au><au>Conidi, Andrea</au><au>Schellens, Ann</au><au>van Dinther, Maarten</au><au>Stubbs, Andrew</au><au>Klippel, Anke</au><au>Huylebroeck, Danny</au><au>ten Dijke, Peter</au><au>Verschueren, Kristin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2009-08-01</date><risdate>2009</risdate><volume>7</volume><issue>8</issue><spage>1342</spage><epage>1353</epage><pages>1342-1353</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Smad2 and Smad3 are intracellular mediators of transforming growth factor β (TGFβ) signaling that share various biochemical
properties, but data emerging from functional analyses in several cell types indicate that these two Smad proteins may convey
distinct cellular responses. Therefore, we have investigated the individual roles of Smad2 and Smad3 in mediating the cytostatic
and proapoptotic effects of TGFβ as well as their function in epithelial-to-mesenchymal transition. For this purpose, we transiently
depleted mouse mammary epithelial cells (Nme) of Smad2 and/or Smad3 mainly by a strategy relying on RNaseH-induced degradation
of mRNA. The effect of such depletion on hallmark events of TGFβ-driven epithelial-to-mesenchymal transition was analyzed,
including dissolution of epithelial junctions, formation of stress fibers and focal adhesions, activation of metalloproteinases,
and transcriptional regulation of acknowledged target genes. Furthermore, we investigated the effect of Smad2 and Smad3 knockdown
on the TGFβ-regulated transcriptome by microarray analysis. Our results identify Smad3 as a key factor to trigger TGFβ-regulated
events and ascribe tumor suppressor as well as oncogenic activities to this protein. (Mol Cancer Res 2009;7(8):1342–53)</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>19671686</pmid><doi>10.1158/1541-7786.MCR-08-0558</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Molecular cancer research, 2009-08, Vol.7 (8), p.1342-1353 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Animals apoptosis Apoptosis - drug effects breast cancer cell proliferation Cell Shape - drug effects Cytoskeleton - drug effects Cytoskeleton - metabolism EMT Enzyme Induction - drug effects Epithelial Cells - drug effects Epithelial Cells - enzymology Epithelial Cells - metabolism Female Gene Expression Profiling Gene Expression Regulation - drug effects Gene Knockdown Techniques GeneBloc Humans Intercellular Junctions - drug effects Intercellular Junctions - metabolism knockdown Mammary Glands, Animal - cytology Matrix Metalloproteinases - biosynthesis Mice Oligonucleotides, Antisense - pharmacology RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction - drug effects siRNA Smad2 Protein - genetics Smad2 Protein - metabolism Smad3 Protein - genetics Smad3 Protein - metabolism Transforming Growth Factor beta - metabolism |
| title | Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells |
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