Protein Kinase C ζ Drives Sphingomyelin Metabolism in the Nucleus During Cell Proliferation

Abstract

Nuclear sphingomyelin is mainly localized in specific lipid microdomains of the inner nuclear membrane in which the active chromatin is attached. Evidence of the presence of PKC ζ in cell nucleus, where it acts on the chromatin remodeling, phosphorylation of histones, formation of the mitotic spindle is increasing. Although the pathway of the sphingomyelin in the cells was described as target of PKC ζ or vice versa the PKC ζ as target of sphingomyelin pathway, the relationship between the two molecules in cell nucleus has not been studied. Here, the possible nuclear PKC ζ / sphingomyelin metabolism enzymes interaction was investigated during liver regeneration. We found that the phosphoPKC ζ and sphingomyelin-synthase increase during the S phase of the cell cycle, while the sphingomyelinase is activated later. The incubation of H35 hepatoma cells with D45262, a compound with 87% PKC ζ inhibitory activity at 10 microM concentration, increases specifically sphingomyelinase and inhibits sphingomyelin-synthase with the reduction of DNA and RNA synthesis as index of the delay of hepatoma cell growth. Current results indicate for the first time the presence of PKC ζ isoform in the nucleus of hepatocytes and hepatoma cells and its relationship with the sphingomyelin metabolism during the S-phase of the cell cycle. Keywords: Hepatoma cells, liver regeneration, nucleus, protein kinase C zeta, neutral-sphingomyelinase, sphingomyelin; sphingomyelin-synthase.