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A gain-of-function mutation in the PDGFR-beta alters thekinetics of injury response in liver and skin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Dept. of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Sweden.
2008 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, 1204-1214 p.Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) isoforms stimulate cell proliferation, migration and survival. We recently generated mice carrying a gain-of-function mutation within the activation loop of PDGF beta-receptor (PDGFR-beta D849N). Embryonic fibroblasts derived from these mice show elevated basal phosphorylation and altered kinetics for ligand-induced activation of PDGFR-beta, as well as enhanced proliferation and migration. To investigate the effect of this mutation in vivo, we used carbon tetrachloride-induced liver injury as a model system. We observed a higher basal activation of mutant PDGFR-beta in unchallenged livers; however, the difference in activation upon carbon tetrachloride stimulation was lower than expected, an effect that might be explained by a delayed response of the mutated receptor toward reactive oxygen species. Mutant mice showed enhanced proliferation of nonparenchymal liver cells and activation of hepatic stellate cells, leading to a small increase in early fibrosis formation. Another mouse strain lacking the binding site for phosphatidylinositol-3' kinase in PDGFR-beta showed the reverse phenotype. These results suggest an important role for PDGFR-beta signaling in the early injury-response. We confirmed this hypothesis with a second injury model, cutaneous wound healing, where we observed earlier proliferation and formation of granulation tissue in D849N-mutant mice.

 

Place, publisher, year, edition, pages
USCAP , 2008. Vol. 88, no 11, 1204-1214 p.
Keyword [en]
Hyperactive PDGFR signaling, mouse models, wound healing
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-103781DOI: 10.1038/labinvest.2008.81ISI: 000260427600007PubMedID: 18762776OAI: oai:DiVA.org:uu-103781DiVA: diva2:218702
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved

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