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Myocardin-related Transcription Factor Regulates Nox4 Protein Expression: LINKING CYTOSKELETAL ORGANIZATION TO REDOX STATE.
Rozycki, Matthew; Bialik, Janne Folke; Speight, Pam; Dan, Qinghong; Knudsen, Teresa E T; Szeto, Stephen G; Yuen, Darren A; Szászi, Katalin; Pedersen, Stine F; Kapus, András.
Afiliación
  • Rozycki M; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.
  • Bialik JF; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, the Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen DK-2100, Denmark.
  • Speight P; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.
  • Dan Q; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.
  • Knudsen TE; the Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen DK-2100, Denmark.
  • Szeto SG; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.
  • Yuen DA; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital.
  • Szászi K; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Departments of Surgery and.
  • Pedersen SF; the Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen DK-2100, Denmark.
  • Kapus A; From the Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Departments of Surgery and Biochemistry, University of Toronto, Toronto, Ontario M5B 1T8, Canada and kapusa@smh.ca.
J Biol Chem ; 291(1): 227-43, 2016 Jan 01.
Article en En | MEDLINE | ID: mdl-26555261
TGFß-induced expression of the NADPH oxidase Nox4 is essential for fibroblast-myofibroblast transition. Rho has been implicated in Nox4 regulation, but the underlying mechanisms are largely unknown. Myocardin-related transcription factor (MRTF), a Rho/actin polymerization-controlled coactivator of serum response factor, drives myofibroblast transition from various precursors. We have shown that TGFß is necessary but insufficient for epithelial-myofibroblast transition in intact epithelia; the other prerequisite is the uncoupling of intercellular contacts, which induces Rho-dependent nuclear translocation of MRTF. Because the Nox4 promoter harbors a serum response factor/MRTF cis-element (CC(A/T)6GG box), we asked if MRTF (and thus cytoskeleton organization) could regulate Nox4 expression. We show that Nox4 protein is robustly induced in kidney tubular cells exclusively by combined application of contact uncoupling and TGFß. Nox4 knockdown abrogates epithelial-myofibroblast transition-associated reactive oxygen species production. Laser capture microdissection reveals increased Nox4 expression in the tubular epithelium also during obstructive nephropathy. MRTF down-regulation/inhibition suppresses TGFß/contact disruption-provoked Nox4 protein and mRNA expression, Nox4 promoter activation, and reactive oxygen species production. Mutation of the CC(A/T)6GG box eliminates the synergistic activation of the Nox4 promoter. Jasplakinolide-induced actin polymerization synergizes with TGFß to facilitate MRTF-dependent Nox4 mRNA expression/promoter activation. Moreover, MRTF inhibition prevents Nox4 expression during TGFß-induced fibroblast-myofibroblast transition as well. Although necessary, MRTF is insufficient; Nox4 expression also requires TGFß-activated Smad3 and TAZ/YAP, two contact- and cytoskeleton-regulated Smad3-interacting coactivators. Down-regulation/inhibition of TAZ/YAP mitigates injury-induced epithelial Nox4 expression in vitro and in vivo. These findings uncover new MRTF- and TAZ/YAP-dependent mechanisms, which link cytoskeleton remodeling and redox state and impact epithelial plasticity and myofibroblast transition.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Citoesqueleto / Regulación Enzimológica de la Expresión Génica / NADPH Oxidasas Límite: Animals Idioma: En Revista: J Biol Chem Año: 2016 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Factores de Transcripción / Citoesqueleto / Regulación Enzimológica de la Expresión Génica / NADPH Oxidasas Límite: Animals Idioma: En Revista: J Biol Chem Año: 2016 Tipo del documento: Article