Activation of the Xmrk proto-oncogene of Xiphophorus by overexpression and mutational alterations
Activation of the Xmrk proto-oncogene of Xiphophorus by overexpression and mutational alterations
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DOI：
10.1038/sj.onc.1201693
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发表时间：
1998-04-02
期刊：
影响因子：
8
通讯作者：
Schartl, M
中科院分区：
文献类型：
--
作者：
Dimitrijevic, N;Winkler, C;Schartl, M
Xmrk是与人EGF受体密切相关的受体酪氨酸激酶，在硬骨鱼剑尾鱼中存在两种形式的Xmrk基因，癌基因（ONC）和原癌基因（INV），而ONC-Xmrk是黑色素瘤诱导基因，INV-Xmrk似乎不参与色素细胞的转化，为了阐明将原癌基因转化为转化癌基因的机制，对两种形式的基因的结构、表达和功能进行了比较分析，与在黑素瘤细胞中以高水平表达的ONC-Xmrk相反，原癌基因INV-Xmrk以非常低的水平普遍表达，表明过表达是ONC-Xmrk致瘤性的一个可能原因。由于原癌基因和癌基因的序列比较揭示了许多氨基酸的变化，确定了这些突变对ONC-Xmrk受体激活的可能影响。发现致癌受体的组成性激活，并且在显微注射到青鳉鱼胚胎中后，INV-Xmrk的异位表达不会导致转基因鱼中的高肿瘤率，如癌基因所观察到的。因此，我们的数据表明，受体单独过表达不足以诱导黑色素瘤，但另外激活ONC-Xmrk突变是其全部致瘤潜力的原因。
Xmrk is a receptor tyrosine kinase closely related to the human EGF receptor, In the teleost fish Xiphophorus two versions of the Xmrk gene exist, an oncogene (ONC) and a proto-oncogene (INV), While ONC-Xmrk is the melanoma-inducing gene, INV-Xmrk appears not to be involved in transformation of pigment cells, To elucidate the mechanism that converts the proto-oncogene into a transforming oncogene a comparative analysis of the structure, expression and function of both versions of the gene was performed, In contrast to ONC-Xmrk which is expressed at high levels in melanoma cells, the protooncogene INV-Xmrk is ubiquitously expressed at very low levels indicating overexpression as one possible reason for tumorigenicity by ONC-Xmrk. As sequence comparison of the proto-oncogene and the oncogene revealed a number of amino acid changes, a possible effect of these mutations on the activation of the ONC-Xmrk receptor was determined, A constitutive activation of the oncogenic receptor was found and ectopic expression of INV-Xmrk after microinjection into medakafish embryos did not lead to the high tumour rate in transgenic fish as observed for the oncogene. Our data therefore suggest that overexpression of the receptor alone is not sufficient for melanoma induction, but that in addition activating mutations in ONC-Xmrk are responsible for its full tumorigenic potential.