Signal transducer and activator of transcription 3 and sphingomyelin metabolism in intranuclear complex during cell proliferation

An "intranuclear complex" characterized by the presence of a new synthesised double-strand RNA stabilized by sphingomyelin and cholesterol has been recently isolated from hepatocyte nuclei. In the present research the existence of STAT3 in the intranuclear complex and its behaviour in relation to cyclin D and sphingomyelin metabolism during liver regeneration were studied with the aim to see if the sphingorryelinase could have a role in cell proliferation. Our data demonstrate that the transcription factor is present in the intranuclear complex either as unphosphorylated or phosphorylated monomeric form. After partial hepatectorny, unphosphorylated STAT3 is very low during G1/S transition of the cell cycle and it increases in correspondence of the of S-phase of the cell cycle when cyclin D1 is reduced. The phosphorylated form increases at the beginning of the S-phase when the neutral sphingomyelinase activity is stimulated with consequent enrichment of ceramide pool. In order to see if the two phenomena could be correlated, the intranuclear complex extracted from normal liver was treated with exogenous sphingomyelinase or ceramide and STAT3 was evaluated. The results show an increase of the phosphorylated transcription factor as happens in liver regeneration, suggesting that sphingomyelinase present in the intranuclear complex is responsible for the STAT3 activation during cell proliferation. (c) 2007 Elsevier Inc. All rights reserved.