p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging.
BACKGROUND
Hepatocyte poliploidization is an age-dependent process, being cytokinesis failure the main mechanism of polyploid hepatocyte formation. Our aim was to study the role of p38α MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging.


METHODS
Wild type and p38α liver-specific knock out mice at different ages (after weaning, adults and old) were used.


RESULTS
We show that p38α MAPK deficiency induces actin disassembly upon aging and also cytokinesis failure leading to enhanced binucleation. Although the steady state levels of cyclin D1 in wild type and p38α knock out old livers remained unaffected, cyclin B1- a marker for G2/M transition- was significantly overexpressed in p38α knock out mice. Our findings suggest that hepatocytes do enter into S phase but they do not complete cell division upon p38α deficiency leading to cytokinesis failure and binucleation. Moreover, old liver-specific p38α MAPK knock out mice exhibited reduced F-actin polymerization and a dramatic loss of actin cytoskeleton. This was associated with abnormal hyperactivation of RhoA and Cdc42 GTPases. Long-term p38α deficiency drives to inactivation of HSP27, which seems to account for the impairment in actin cytoskeleton as Hsp27-silencing decreased the number and length of actin filaments in isolated hepatocytes.


CONCLUSIONS
p38α MAPK is essential for actin dynamics with age in hepatocytes.
Department of Physiology, University of Valencia. Burjassot, Valencia, Spain.
Ana M
AM
Tormos
Department of Physiology, University of Valencia. Burjassot, Valencia, Spain.
Sergio
S
Rius-Pérez
Department of Physiology, University of Valencia. Burjassot, Valencia, Spain.
María
M
Jorques
Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain.
Patricia
P
Rada
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.
Lorena
L
Ramirez
Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), Arturo Duperier 4, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain.
Ángela M
ÁM
Valverde
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Ángel R
ÁR
Nebreda
Department of Physiology, University of Valencia. Burjassot, Valencia, Spain.
Juan
J
Sastre
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia. Burjassot, Valencia, Spain.
Raquel
http://orcid.org/0000-0002-9816-9693
R
Taléns-Visconti
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D016922:Cellular Senescence; D048749:Cytokinesis / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism*; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D000199:Actins; D015415:Biomarkers; C106281:Mknk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048308:Mitogen-Activated Protein Kinase 14