Abstract
Extensive studies of primary tumors and tumor derived cell lines revealed that inappropriate activation of specific STATs (particularly of STAT3 and STAT5) occurs with high frequency in a wide variety of human cancers. We reported recently that the melanoma inducing EGFR-related receptor Xmrk specifically induces constitutive activation of STAT5 in fish melanoma cells. However, little is known about the role of STAT5 in solid tumours in general and its function in melanoma in particular. Recent examinations suggest that activated STAT signalling participates in oncogenesis by stimulating cell proliferation and preventing apoptosis. As an initial approach to understanding the consequences of Xmrk induced STAT5 signalling we used the well characterized pro B-cell line Ba/F3 as a sensitive system to analyse mitogenic as well as anti-apoptotic signalling. We identified STAT5 activation as being involved in both growth and survival signalling triggered by the Xmrk kinase possibly due to STAT5 induced expression of pim-1 and bcl-x. We also found a new mechanism of activation of STAT5 by receptor tyrosine kinases, whereby direct interaction of the receptor kinase domain with the STAT protein in a phosphotyrosine independent way led to activation of STAT5 in terms of DNA binding and target gene expression.
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Acknowledgements
We thank Petra Fisher for excellent technical assistance, Jakob Troppmair for the BaF3-ΔStuI-LIDEMANE cells, Fabrice Gouilleux for the bcl-x plasmid, and the Resource Centre of the German Human Genome Project for the c-myc EST/IMAGE clone. This work was supported by grants to M Schartl supplied by the European Union (EU), grant no. FAIR PL 95-666 and the Deutsche Forschungsgemeinschaft through the SFB 487 (‘Regulatorische Membranproteine’) and the SFB 465 (‘Entwicklung und Manipulation pluripotenter Zellen’). E Geissinger was supported by a fellowship of the Graduiertenkolleg ‘Regulation des Zellwachstums’.
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Morcinek, J., Weisser, C., Geissinger, E. et al. Activation of STAT5 triggers proliferation and contributes to anti-apoptotic signalling mediated by the oncogenic Xmrk kinase. Oncogene 21, 1668–1678 (2002). https://doi.org/10.1038/sj.onc.1205148
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DOI: https://doi.org/10.1038/sj.onc.1205148
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