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

Marcin Kortylewski, Peter C. Heinrich, Andrzej Mackiewicz, Ute Schniertshauer, Ursula Klingmüller, Koichi Nakajima, Toshio Hirano, Friedemann Horn, Iris Behrmann

    Research output: Contribution to journalArticle

    117 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)3742-3753
    Number of pages12
    JournalOncogene
    Volume18
    Issue number25
    DOIs
    StatePublished - Jun 24 1999

    Keywords

    • Growth arrest
    • Interleukin-6
    • Melanoma
    • Oncostatin M
    • STAT
    • p27/Kip

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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    Kortylewski, M., Heinrich, P. C., Mackiewicz, A., Schniertshauer, U., Klingmüller, U., Nakajima, K., Hirano, T., Horn, F., & Behrmann, I. (1999). 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. Oncogene, 18(25), 3742-3753. https://doi.org/10.1038/sj.onc.1202708