Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions
The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxym...
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description | The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear beta-catenin and reduced phospho-beta-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3beta (GSK-3beta) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional beta-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis. |
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To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear beta-catenin and reduced phospho-beta-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3beta (GSK-3beta) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional beta-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0008507</identifier><identifier>PMID: 20084281</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adherens junctions ; Adherens Junctions - immunology ; Adherens Junctions - physiology ; Adhesive strength ; AKT protein ; Animals ; Azoxymethane ; Base Sequence ; beta Catenin - metabolism ; Carcinogenesis ; Carcinogens ; Cell adhesion & migration ; Cell Biology/Cell Adhesion ; Colitis ; Colitis - physiopathology ; Colorectal cancer ; Colorectal carcinoma ; Comparative analysis ; Copy number ; Deactivation ; Dextran ; Dextrans ; DNA Primers ; E-cadherin ; Enterocytes ; Enzyme-Linked Immunosorbent Assay ; Epidermal growth factor ; Epithelial cells ; G protein-coupled receptors ; Gastroenterology and Hepatology/Colon and Rectum ; Gastroenterology and Hepatology/Inflammatory Bowel Disease ; Genetic engineering ; Glycogen ; Glycogen synthase kinase 3 ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; Inactivation ; Inflammatory bowel disease ; Intestinal Mucosa - enzymology ; Intestinal Mucosa - immunology ; Intestinal Mucosa - metabolism ; Intestine ; Kinases ; Membrane Glycoproteins - immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron ; Proto-Oncogene Proteins c-akt - metabolism ; Rodents ; Signal Transduction ; Sodium ; Sodium sulfate ; Structural integrity ; Sulfate ; Sulfates ; Tight junctions ; Transgenic mice ; Tumorigenesis ; β-Catenin</subject><ispartof>PloS one, 2010-01, Vol.5 (1), p.e8507</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Becker 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. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Becker et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c789t-b67f90c36c7171a7e496cd8fa65fd184a2f63d7acbb0f942f259061284c439233</citedby><cites>FETCH-LOGICAL-c789t-b67f90c36c7171a7e496cd8fa65fd184a2f63d7acbb0f942f259061284c439233</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/PMC2801611/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801611/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20084281$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Becker, Susann</creatorcontrib><creatorcontrib>Wandel, Elke</creatorcontrib><creatorcontrib>Wobus, Manja</creatorcontrib><creatorcontrib>Schneider, Rick</creatorcontrib><creatorcontrib>Amasheh, Salah</creatorcontrib><creatorcontrib>Sittig, Doreen</creatorcontrib><creatorcontrib>Kerner, Christiane</creatorcontrib><creatorcontrib>Naumann, Ronald</creatorcontrib><creatorcontrib>Hamann, Joerg</creatorcontrib><creatorcontrib>Aust, Gabriela</creatorcontrib><title>Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear beta-catenin and reduced phospho-beta-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3beta (GSK-3beta) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional beta-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.</description><subject>Adherens junctions</subject><subject>Adherens Junctions - immunology</subject><subject>Adherens Junctions - physiology</subject><subject>Adhesive strength</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Azoxymethane</subject><subject>Base Sequence</subject><subject>beta Catenin - metabolism</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology/Cell Adhesion</subject><subject>Colitis</subject><subject>Colitis - physiopathology</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Comparative analysis</subject><subject>Copy number</subject><subject>Deactivation</subject><subject>Dextran</subject><subject>Dextrans</subject><subject>DNA Primers</subject><subject>E-cadherin</subject><subject>Enterocytes</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Epidermal growth factor</subject><subject>Epithelial cells</subject><subject>G protein-coupled receptors</subject><subject>Gastroenterology and Hepatology/Colon and Rectum</subject><subject>Gastroenterology and Hepatology/Inflammatory Bowel Disease</subject><subject>Genetic engineering</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Inactivation</subject><subject>Inflammatory bowel disease</subject><subject>Intestinal Mucosa - enzymology</subject><subject>Intestinal Mucosa - immunology</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestine</subject><subject>Kinases</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Electron</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Sodium</subject><subject>Sodium sulfate</subject><subject>Structural integrity</subject><subject>Sulfate</subject><subject>Sulfates</subject><subject>Tight junctions</subject><subject>Transgenic mice</subject><subject>Tumorigenesis</subject><subject>β-Catenin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11r2zAUhs3YWLtu_2BshsHGLpJJtixZN4OSfQUKgX3dCkU-chQcKbXk0l7tr--kSUs8ejFssJCf8772e3Sy7CUlU1oK-mEdht7rbroNHqaEkLoi4lF2SmVZTHhBysdH65PsWYxrQqqy5vxpdlIgzoqanmZ_FlfQw_W2hxhd8Hmw-eyTFLnzeCeIyaFHDluXVtA5XBrourjDUq99bME7k2-cgVynBH7QWJOb0LnkYr68yWPqwbdY7J1vc92s0M3HfD14k9AvPs-eWN1FeHF4nmW_vnz-Ofs2uVh8nc_OLyZG1DJNllxYSUzJjaCCagFMctPUVvPKNrRmurC8bIQ2yyWxkhW2qCThtKiZYaUsyvIse73X3XYhqkN2USEhi0pIxpGY74km6LXa9m6j-xsVtFO3G6Fvle6TMx0ogzZMmBI0VCgPy4YbraUsrG0sqWrU-nhwG5YbaAx4TKsbiY7feLdSbbhSRU0opxQF3h0E-nA5YBvUxsVd9NpDGKISjHFZCUaQfPMP-fDPHahW4_c7bwPamp2mOmcCE6KUV0hNH6DwagBbjOfMOtwfFbwfFSCT4Dq1eohRzX98_3928XvMvj1iV6C7tIqhG26PzBhke9D0IcYe7H3GlKjdmNyloXZjog5jgmWvjvtzX3Q3F-Vf6SAP-w</recordid><startdate>20100113</startdate><enddate>20100113</enddate><creator>Becker, Susann</creator><creator>Wandel, Elke</creator><creator>Wobus, Manja</creator><creator>Schneider, Rick</creator><creator>Amasheh, Salah</creator><creator>Sittig, Doreen</creator><creator>Kerner, Christiane</creator><creator>Naumann, Ronald</creator><creator>Hamann, Joerg</creator><creator>Aust, Gabriela</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>5PM</scope><scope>DOA</scope></search><sort><creationdate>20100113</creationdate><title>Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions</title><author>Becker, Susann ; Wandel, Elke ; Wobus, Manja ; Schneider, Rick ; Amasheh, Salah ; Sittig, Doreen ; Kerner, Christiane ; Naumann, Ronald ; Hamann, Joerg ; Aust, Gabriela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c789t-b67f90c36c7171a7e496cd8fa65fd184a2f63d7acbb0f942f259061284c439233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adherens junctions</topic><topic>Adherens Junctions - immunology</topic><topic>Adherens Junctions - physiology</topic><topic>Adhesive strength</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Azoxymethane</topic><topic>Base Sequence</topic><topic>beta Catenin - metabolism</topic><topic>Carcinogenesis</topic><topic>Carcinogens</topic><topic>Cell adhesion & migration</topic><topic>Cell Biology/Cell Adhesion</topic><topic>Colitis</topic><topic>Colitis - physiopathology</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Comparative analysis</topic><topic>Copy number</topic><topic>Deactivation</topic><topic>Dextran</topic><topic>Dextrans</topic><topic>DNA Primers</topic><topic>E-cadherin</topic><topic>Enterocytes</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Epidermal growth factor</topic><topic>Epithelial cells</topic><topic>G protein-coupled receptors</topic><topic>Gastroenterology and Hepatology/Colon and Rectum</topic><topic>Gastroenterology and Hepatology/Inflammatory Bowel Disease</topic><topic>Genetic engineering</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogen Synthase Kinase 3 - 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To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear beta-catenin and reduced phospho-beta-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3beta (GSK-3beta) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional beta-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20084281</pmid><doi>10.1371/journal.pone.0008507</doi><tpages>e8507</tpages><oa>free_for_read</oa></addata></record> |
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recordid | cdi_plos_journals_1289257946 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
subjects | Adherens junctions Adherens Junctions - immunology Adherens Junctions - physiology Adhesive strength AKT protein Animals Azoxymethane Base Sequence beta Catenin - metabolism Carcinogenesis Carcinogens Cell adhesion & migration Cell Biology/Cell Adhesion Colitis Colitis - physiopathology Colorectal cancer Colorectal carcinoma Comparative analysis Copy number Deactivation Dextran Dextrans DNA Primers E-cadherin Enterocytes Enzyme-Linked Immunosorbent Assay Epidermal growth factor Epithelial cells G protein-coupled receptors Gastroenterology and Hepatology/Colon and Rectum Gastroenterology and Hepatology/Inflammatory Bowel Disease Genetic engineering Glycogen Glycogen synthase kinase 3 Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta Inactivation Inflammatory bowel disease Intestinal Mucosa - enzymology Intestinal Mucosa - immunology Intestinal Mucosa - metabolism Intestine Kinases Membrane Glycoproteins - immunology Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Electron Proto-Oncogene Proteins c-akt - metabolism Rodents Signal Transduction Sodium Sodium sulfate Structural integrity Sulfate Sulfates Tight junctions Transgenic mice Tumorigenesis β-Catenin |
title | Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T22%3A11%3A44IST&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=Overexpression%20of%20CD97%20in%20intestinal%20epithelial%20cells%20of%20transgenic%20mice%20attenuates%20colitis%20by%20strengthening%20adherens%20junctions&rft.jtitle=PloS%20one&rft.au=Becker,%20Susann&rft.date=2010-01-13&rft.volume=5&rft.issue=1&rft.spage=e8507&rft.pages=e8507-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0008507&rft_dat=%3Cgale_plos_%3EA473921165%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=1289257946&rft_id=info:pmid/20084281&rft_galeid=A473921165&rft_doaj_id=oai_doaj_org_article_ccbb47c3eae5439ebd6caa992ffdf058&rfr_iscdi=true |