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

Oncogene volume 19, pages 3675–3683 (2000)Cite this article

Abstract

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 Inhibitory 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 phosphorylation 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. These processes were accompanied by a decrease in cyclin A expression and CDK2 activity, and enhanced accumulation of p27kip1. The level of p27kip1 mRNA expression was unaffected by the cytokines, and maintenance of the elevated level of p27kip1 occurred independently of de novo protein synthesis. Furthermore, inhibition of proteasomal activity increased the level of p27kip1 in the unstimulated cells to the same level as in OSM-treated cells. Inhibition of MEK activation completely abrogated OSM and IL-6 induced p27kip1 accumulation, while expression of dominant negative STAT5 decreased the OSM and IL-6 mediated inhibition of DNA-synthesis and partially inhibited p27kip1 accumulation.

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Acknowledgements

We thank Dr Jiri Bartek and Dr Jiri Lukas, The Danish Cancer Society, Denmark for giving helpful advice, Schering-Plough Research Institute for providing recombinant human (rhu) IL-10, Sandoz for rhu IL-6, Immunex Corporation for OSM, and Genetics Institute for IL-6. This work was supported by The Danish Cancer Society grant 96109 to J Jurlander and NIH grant CA 26122 to H Baumann.

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  1. Department of Haematology, The Leukaemia and Lymphoma Marker Laboratory L4041, The Finsen Centre, Rigshospitalet, Blegdamsvej 9, Copenhagen, DK-2100, Denmark

    Pia Klausen, Lone Pedersen & Jesper Jurlander

  2. The Department of Molecular and Cell Biology, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, 14263, New York, NY, USA

    Heinz Baumann

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  1. Pia Klausen
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Klausen, P., Pedersen, L., Jurlander, J. et al. Oncostatin M and Interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells. Oncogene 19, 3675–3683 (2000). https://doi.org/10.1038/sj.onc.1203707

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