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    Keywords: EXPRESSION ; CELL-PROLIFERATION ; cell cycle ; CELL-CYCLE ; OVEREXPRESSION ; FIBRILLARY ACIDIC PROTEIN ; MICE LACKING VIMENTIN ; INTERMEDIATE-FILAMENT NETWORKS ; UBIQUITIN-PROTEASOME PATHWAY ; LACERATED CORNEAS ; MUSCLE ALPHA-ACTIN ; MYOFIBROBLAST DIFFERENTIATION ; RETINAL-DETACHMENT ; WITHAFERIN-A
    Abstract: The type III intermediate filaments (IFs) are essential cytoskeletal elements of mechanosignal transduction and serve critical roles in tissue repair. Mice genetically deficient for the IF protein vimentin (Vim(-/-)) have impaired wound healing from deficits in myofibroblast development. We report a surprising finding made in Vim(-/-) mice that corneas are protected from fibrosis and instead promote regenerative healing after traumatic alkali injury. This reparative phenotype in Vim(-/-) corneas is strikingly recapitulated by the pharmacological agent withaferin A (WFA), a small molecule that binds to vimentin and downregulates its injury-induced expression. Attenuation of corneal fibrosis by WFA is mediated by downregulation of ubiquitin conjugating E3 ligase Skp2 and upregulation of cyclin-dependent kinase inhibitors (CKIs) p27(Kip1) and p21(Cip1). In cell culture models, WFA exerts G2/M cell cycle arrest in a p27(Kip1) and Skp2-dependent manner. Finally, by developing a highly sensitive imaging method to measure corneal opacity, we identify a novel role for desmin overexpression in corneal haze. We demonstrate that desmin downregulation by WFA via targeting the conserved WFA-ligand binding site shared among type III IFs promotes further improvement of corneal transparency without affecting CKI levels in Vim(-/-) mice. This dissociates a direct role for desmin in corneal cell proliferation. Taken together, our findings illuminate a previously unappreciated pathogenic role for type III IF overexpression in corneal fibrotic conditions and also validate WFA as a powerful drug lead towards anti-fibrosis therapeutic development.
    Type of Publication: Journal article published
    PubMed ID: 22117063
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