title: p38α deficiency and oxidative stress cause cytokinesis failure in hepatocytes.
abstract: Cytokinesis is the last step in mitosis and it implies re-organization of the actin cytoskeleton. Its failure is one of the major mechanisms of polyploidy and binucleation in mammals. Our aims were 1) to assess the role of redox-sensitive p38α MAPK in cytokinesis by studying the liver of wild type mice or liver-specific p38α knock-out mice; 2) to assess the role of oxidative stress associated with hepatocyte isolation on cytokinesis. When p38α was down-regulated in hepatocytes, MK2 phosphorylation on threonine 334 was completely abrogated. Activation of MNK-1, required for abscission of the intercellular bridge, was diminished. Key proteins of the RhoA pathway (phospho-PRK2, nuclear phosphorylated cofilin, and cytosolic p27) were assessed confirming the impairment of this pathway. The absence of p38α in aging liver also led to a decrease in HSP27 phosphorylation, which is required for actin polymerization. Indeed, a severe impairment in the F-actin filamentous structure was found in the liver of old mice upon p38α deficiency. Consequently, long-term p38α MAPK down-regulation markedly affects the RhoA pathway and actin cytoskeleton dynamics inducing actin disassembly and cytokinesis failure upon aging. On the other hand, hepatocyte isolation caused marked glutathione depletion, increased generation of reactive oxygen species, and activated cell cycle entry. Addition of N-acetyl cysteine to isolation media prevented glutathione depletion, restrained the cell cycle entry, and abrogated defective cytokinesis and the formation of binucleated hepatocytes during isolation. Our results show that hepatocytes do enter into S phase but they do not complete cell division with age upon p38α deficiency or upon oxidative stress associated with isolation leading in both cases to cytokinesis failure and binucleation.
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Tormos Ana
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Taléns-Visconti
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Jorques
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Pérez-Garrido
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bonora-Centelles
authors.affiliation: Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Nebreda Ángel
authors.affiliation: University of Valencia (Faculty of Pharmacy), Department of Pharmacy and Pharmaceutical Technology, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre