p38[alpha] 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- a marker for G2/M transition- was significantly overexpressed in p38[alpha] knock out mice. Our findings suggest that hepatocytes do enter into S phase but they do not complete cell division upon p38[alpha] 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.