title: Loss of γ-cytoplasmic actin triggers myofibroblast transition of human epithelial cells.
abstract: Transdifferentiation of epithelial cells into mesenchymal cells and myofibroblasts plays an important role in tumor progression and tissue fibrosis. Such epithelial plasticity is accompanied by dramatic reorganizations of the actin cytoskeleton, although mechanisms underlying cytoskeletal effects on epithelial transdifferentiation remain poorly understood. In the present study, we observed that selective siRNA-mediated knockdown of γ-cytoplasmic actin (γ-CYA), but not β-cytoplasmic actin, induced epithelial-to-myofibroblast transition (EMyT) of different epithelial cells. The EMyT manifested by increased expression of α-smooth muscle actin and other contractile proteins, along with inhibition of genes responsible for cell proliferation. Induction of EMyT in γ-CYA-depleted cells depended on activation of serum response factor and its cofactors, myocardial-related transcriptional factors A and B. Loss of γ-CYA stimulated formin-mediated actin polymerization and activation of Rho GTPase, which appear to be essential for EMyT induction. Our findings demonstrate a previously unanticipated, unique role of γ-CYA in regulating epithelial phenotype and suppression of EMyT that may be essential for cell differentiation and tissue fibrosis.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Susana
authors.initials: S
authors.lastname: Lechuga
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Somesh
authors.initials: S
authors.lastname: Baranwal
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: Nayden G
authors.initials: NG
authors.lastname: Naydenov
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298.
authors.forename: John F
authors.initials: JF
authors.lastname: Kuemmerle
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia.
authors.forename: Vera
authors.initials: V
authors.lastname: Dugina
authors.affiliation: Department of Pathology and Immunology, University Medical Center, University of Geneva, Geneva 4, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Chaponnier
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298 Virginia Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298 VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 aivanov2@vcu.edu.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Ivanov
mesh_terms: D000199:Actins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D058628:Myofibroblasts / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism
chemical_list: D000199:Actins; D026362:Serum Response Factor