Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation.
Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation.
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干扰 ERK1 和 ERK2 的组成型激活会损害 EWS/FLI-1 依赖性转化。
DOI：
10.1038/sj.onc.1203811
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发表时间：
2000
期刊：
影响因子：
8
通讯作者：
IlariaJr,RL
中科院分区：
文献类型：
--
作者：
Silvany,RE;Eliazer,S;Wolff,NC;IlariaJr,RL
嵌合基因EWS/ fl -1是尤文氏肉瘤和原始神经外胚层肿瘤家族的标志，其编码的融合蛋白具有增强的转录激活特性和保留对典型ETS结合位点的识别。虽然EWS/ fl -1可以改变多种基因的表达，但EWS/ fl -1作为致癌基因的确切机制仍有待明确。在这项研究中，我们报道了丝裂原活化蛋白激酶（MAPK）信号通路的成员ERK1和ERK2在表达EWS/ fl -1的NIH 3T3细胞中被组成性激活。通过高度特异性的MEK1抑制剂或显性ras阴性突变体干扰ERK激活，严重损害了EWS/ fl -1转化NIH3T3细胞在半固体培养基中生长的能力。EWS/FLI-1突变体在dna结合和转录激活方面存在缺陷，无法激活ERK，并且在3T3细胞转化中也存在缺陷。在几种人类尤文氏肉瘤肿瘤来源的细胞系中，组成型ERK活化也很明显。有趣的是，与表达更常见的I型融合的细胞相比，表达II型EWS/ fl -1融合的细胞在转录激活方面表现出更强的活性，甚至表现出更大的MAPK激活。这些结果暗示了ERK在EWS/ fl -1转化过程中的激活，并提示该信号通路可能在Ewing肉瘤的发病机制中起重要作用。
The chimeric gene EWS/FLI-1, the hallmark of the Ewing's sarcoma and primitive neuroectodermal tumor family, encodes a fusion protein with enhanced transcriptional activation properties and preserved recognition of canonical ETS binding sites. Although EWS/FLI-1 alters the expression of various genes, the precise mechanism by which EWS/FLI-1 acts as an oncogene remains to be defined. In this study we report that members of the mitogen-activated protein kinase (MAPK) signaling pathway, ERK1 and ERK2, are constitutively activated in NIH 3T3 cells expressing EWS/FLI-1. Interference with ERK activation by either highly specific inhibitors of MEK1 or a dominant negative ras mutant profoundly impaired the ability of EWS/FLI-1 to transform NIH3T3 cells to growth in semi-solid medium. An EWS/FLI-1 mutant defective in DNA-binding and transcriptional activation failed to activate ERK and was also defective in 3T3 cell transformation. Constitutive ERK activation was also evident in several human Ewing's sarcoma tumor-derived cell lines. Interestingly, cells expressing the type II EWS/FLI-1 fusion, recently demonstrated more potent in transcriptional activation, showed even greater MAPK activation than cells expressing the more common type I fusion. These results implicate ERK activation in EWS/FLI-1 transformation and suggest that this signaling pathway may be important in the pathogenesis of Ewing's sarcoma.