FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing.
Following damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including c...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3160839?pdf=render |
| _version_ | 1818957568507117568 |
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| author | Katherine A Owen Michelle Y Abshire Robert W Tilghman James E Casanova Amy H Bouton |
| author_facet | Katherine A Owen Michelle Y Abshire Robert W Tilghman James E Casanova Amy H Bouton |
| author_sort | Katherine A Owen |
| collection | DOAJ |
| description | Following damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including cell migration, proliferation and survival. However, few studies to date have determined how FAK contributes to mucosal wound healing in vivo.To examine the role of FAK in intestinal epithelial homeostasis and during injury, we generated intestinal epithelium (IE)-specific conditional FAK knockout mice. Colitis was induced with dextran-sulfate-sodium (DSS) and intestinal tissues were analyzed by immunohistochemistry and immunoblotting. While intestinal development occurred normally in mice lacking FAK, FAK-deficient animals were profoundly susceptible to colitis. The loss of epithelial FAK resulted in elevated p53 expression and an increased sensitivity to apoptosis, coincident with a failure to upregulate epithelial cell proliferation. FAK has been reported to function as a mechanosensor, inducing cyclin D1 expression and promoting cell cycle progression under conditions in which tissue/matrix stiffness is increased. Collagen deposition, a hallmark of inflammatory injury resulting in increased tissue rigidity, was observed in control and FAK knockout mice during colitis. Despite this fibrotic response, the colonic epithelium in FAK-deficient mice exhibited significantly reduced cyclin D1 expression, suggesting that proliferation is uncoupled from fibrosis in the absence of FAK. In support of this hypothesis, proliferation of Caco-2 cells increased proportionally with matrix stiffness in vitro only under conditions of normal FAK expression; FAK depleted cells exhibited reduced proliferation concomitant with attenuated cyclin D1 expression.In the colon, FAK functions as a regulator of epithelial cell survival and proliferation under conditions of mucosal injury and a mechanosensor of tissue compliance, inducing repair-driven proliferation in the colonic epithelium through upregulation of cyclin D1. |
| first_indexed | 2024-12-20T11:11:55Z |
| format | Article |
| id | doaj.art-32a3398e065841ca9677d4d18c14e8b2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T11:11:55Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-32a3398e065841ca9677d4d18c14e8b22022-12-21T19:42:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0168e2312310.1371/journal.pone.0023123FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing.Katherine A OwenMichelle Y AbshireRobert W TilghmanJames E CasanovaAmy H BoutonFollowing damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including cell migration, proliferation and survival. However, few studies to date have determined how FAK contributes to mucosal wound healing in vivo.To examine the role of FAK in intestinal epithelial homeostasis and during injury, we generated intestinal epithelium (IE)-specific conditional FAK knockout mice. Colitis was induced with dextran-sulfate-sodium (DSS) and intestinal tissues were analyzed by immunohistochemistry and immunoblotting. While intestinal development occurred normally in mice lacking FAK, FAK-deficient animals were profoundly susceptible to colitis. The loss of epithelial FAK resulted in elevated p53 expression and an increased sensitivity to apoptosis, coincident with a failure to upregulate epithelial cell proliferation. FAK has been reported to function as a mechanosensor, inducing cyclin D1 expression and promoting cell cycle progression under conditions in which tissue/matrix stiffness is increased. Collagen deposition, a hallmark of inflammatory injury resulting in increased tissue rigidity, was observed in control and FAK knockout mice during colitis. Despite this fibrotic response, the colonic epithelium in FAK-deficient mice exhibited significantly reduced cyclin D1 expression, suggesting that proliferation is uncoupled from fibrosis in the absence of FAK. In support of this hypothesis, proliferation of Caco-2 cells increased proportionally with matrix stiffness in vitro only under conditions of normal FAK expression; FAK depleted cells exhibited reduced proliferation concomitant with attenuated cyclin D1 expression.In the colon, FAK functions as a regulator of epithelial cell survival and proliferation under conditions of mucosal injury and a mechanosensor of tissue compliance, inducing repair-driven proliferation in the colonic epithelium through upregulation of cyclin D1.http://europepmc.org/articles/PMC3160839?pdf=render |
| spellingShingle | Katherine A Owen Michelle Y Abshire Robert W Tilghman James E Casanova Amy H Bouton FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. PLoS ONE |
| title | FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. |
| title_full | FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. |
| title_fullStr | FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. |
| title_full_unstemmed | FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. |
| title_short | FAK regulates intestinal epithelial cell survival and proliferation during mucosal wound healing. |
| title_sort | fak regulates intestinal epithelial cell survival and proliferation during mucosal wound healing |
| url | http://europepmc.org/articles/PMC3160839?pdf=render |
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