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| 24 June 1999, Volume 18, Number 25, Pages 3742-3753 |
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| Article |
| Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1 |
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| Marcin Kortylewski1,2, Peter C Heinrich1, Andrzej Mackiewicz2, Ute Schniertshauer1, Ursula Klingmüller3, Koichi Nakajima4, Toshio Hirano4, Friedemann Horn5 and Iris Behrmann1 |
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1Department of Biochemistry, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
2Department of Cancer Immunology, University School of Medical Sciences, Garbary St. 15, 61866 Poznan, Poland
3Max-Planck-Institute for Immunobiology, Spemann Laboratory, Stübeweg 51, 79108 Freiburg, Germany
4Department of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565, Japan
5Institute of Clinical Immunology and Transfusion Medicine, Section Molecular Immunology, University of Leipzig, Delitzscher Str. 141, 04129 Leipzig, Germany
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Correspondence to: Iris Behrmann, Department of Biochemistry, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
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| Abstract |
| Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this effect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 effectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory effect of OSM and IL-6 in A375 cells. In addition, we have identified the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines. |
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| Keywords |
| melanoma; STAT; interleukin-6; oncostatin M; p27/Kip; growth arrest |
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| Received 3 November 1998; revised 19 January 1999; accepted 19 January 1999 |
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| 24 June 1999, Volume 18, Number 25, Pages 3742-3753 |
| Table of contents Previous Abstract Next Full text PDF |
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