title: miR-218 regulates focal adhesion kinase-dependent TGFβ signaling in fibroblasts.
abstract: Scarring, which occurs in essentially all adult tissue, is characterized by the excessive production and remodeling of extracellular matrix by α-smooth muscle actin (SMA)-expressing myofibroblasts located within connective tissue. Excessive scarring can cause organ failure and death. Oral gingivae do not scar. Compared to dermal fibroblasts, gingival fibroblasts are less responsive to transforming growth factor β (TGFβ) due to the reduced expression, due to the reduced expression and activity of focal adhesion kinase (FAK) by this cell type. Here we show that, compared with dermal fibroblasts, gingival fibroblasts show reduced expression of miR-218. Introduction of pre-miR-218 into gingival fibroblasts elevates FAK expression and, via a FAK/src-dependent mechanism, results in the ability of TGFβ to induce α-SMA. The deubiquitinase cezanne is a direct target of miR-218 and has increased expression in gingival fibroblasts compared with dermal fibroblasts. Knockdown of cezanne in gingival fibroblasts increases FAK expression and causes TGFβ to induce α-smooth muscle actin (α-SMA). These results suggest that miR-218 regulates the ability of TGFβ to induce myofibroblast differentiation in fibroblasts via cezanne/FAK.
authors: Department of Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada London Regional Genomics Centre Microarray Facility, Robarts Research Institute, London, ON N6A 5K8, Canada.
authors: Fen
authors: F
authors: Guo
authors: David E
authors: DE
authors: Carter
authors: Andrew
authors: A
authors: Leask
mesh_terms: D000199:Actins / Q000378:metabolism; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D016000:Cluster Analysis; D020405:Dermis / Q000166:cytology; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005881:Gingiva / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D005353:Fibronectins; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D051416:Focal Adhesion Protein-Tyrosine Kinases; D010450:Endopeptidases; C476458:OTUD7B protein, human