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 p38 alpha MAPK in the regulation of actin cytoskeleton and cytokinesis in hepatocytes during development and aging. Methods Wild type and p38 alpha liver-specific knock out mice at different ages (after weaning, adults and old) were used. Results We show that p38 alpha 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 p38 alpha knock out old livers remained unaffected, cyclin B1-alpha marker for G2/M transition-was significantly overexpressed in p38a knock out mice. Our findings suggest that hepatocytes do enter into S phase but they do not complete cell division upon p38 alpha a deficiency leading to cytokinesis failure and binucleation. Moreover, old liver-specific p38 alpha 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 p38 alpha 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 p38 alpha MAPK is essential for actin dynamics with age in hepatocytes.