Oncostatin M and Interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells

We analysed the regulation of G1-phase progression in relation to cytokine receptor signalling in HepG2 hepatoma cells, stably transduced with the IL- 10 receptor after stimulation with Oncostatin M (OSM), IL-6. Leukaemia Inhi bitory Factor (LIF) and IL-10. All cytokines induced STAT3 phosphorylation to approximately the same level, but only OSM, and to a lesser extent IL-6, induced STAT5 phosphorylation. The cytokines also stimulated phosphorylati on of ERK in the order of decreasing effectiveness: OSM>IL-6>LIF>IL-10. The same order of activity of the cytokines was observed on inhibition of DNA synthesis and accumulation of cells in the G1-phase of the cell cycle. Thes e processes were accompanied by a decrease in cyclin A expression and CDK2 activity, and enhanced accumulation of p27kip1. The level of p27kip1 mRNA e xpression was unaffected by the cytokines, and maintenance of the elevated level of p27kip1 occurred independently of de novo protein synthesis. Furth ermore, inhibition of proteasomal activity increased the level of p27kip1 i n the unstimulated cells to the same level as in OSM-treated cells. Inhibit ion of MEK activation completely abrogated OSM and IL-6 induced p27kip1 acc umulation, while expression of dominant negative STAT5 decreased the OSM an d IL-6 mediated inhibition of DNA-synthesis and partially inhibited p27kip1 accumulation.