Activation of STAT5 triggers proliferation and contributes to anti-apoptotic signalling mediated by the oncogenic Xmrk kinase
Activation of STAT5 triggers proliferation and contributes to anti-apoptotic signalling mediated by the oncogenic Xmrk kinase
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DOI：
10.1038/sj.onc.1205148
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发表时间：
2002-03-07
期刊：
影响因子：
8
通讯作者：
Wellbrock, C
中科院分区：
文献类型：
--
作者：
Morcinek, JC;Weisser, C;Wellbrock, C
对原发性肿瘤和肿瘤衍生细胞系的广泛研究揭示，在多种人类癌症中，特异性STAT（特别是STAT 3和STAT 5）的不适当活化以高频率发生。我们最近报道了黑色素瘤诱导EGFR相关受体Xmrk特异性诱导鱼类黑色素瘤细胞中STAT 5的组成性激活。然而.关于STAT 5在实体瘤中的作用，特别是其在黑色素瘤中的功能，人们知之甚少。最近的研究表明，激活的STAT信号通过刺激细胞增殖和阻止细胞凋亡参与肿瘤发生。作为理解Xmrk诱导的STAT 5信号传导的后果的初始方法，我们使用充分表征的原B细胞系Ba/F3作为分析促有丝分裂以及抗凋亡信号传导的敏感系统。我们确定STAT 5激活参与由Xmrk激酶触发的生长和存活信号传导，这可能是由于STAT 5诱导phnI和bcl-x的表达。我们还发现了受体酪氨酸激酶激活STAT 5的新机制，由此受体激酶结构域与STAT蛋白以磷酸酪氨酸非依赖性方式直接相互作用导致STAT 5在DNA结合和靶基因表达方面的激活。
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 phnI 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.