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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Veröffentlicht in:PloS one 2010-01, Vol.5 (1), p.e8507
Hauptverfasser: Becker, Susann, Wandel, Elke, Wobus, Manja, Schneider, Rick, Amasheh, Salah, Sittig, Doreen, Kerner, Christiane, Naumann, Ronald, Hamann, Joerg, Aust, Gabriela
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creator Becker, Susann
Wandel, Elke
Wobus, Manja
Schneider, Rick
Amasheh, Salah
Sittig, Doreen
Kerner, Christiane
Naumann, Ronald
Hamann, Joerg
Aust, Gabriela
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. 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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. 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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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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