EWING SARCOMA 11-22 TRANSLOCATION PRODUCES A CHIMERIC TRANSCRIPTION FACTOR THAT REQUIRES THE DNA-BINDING DOMAIN ENCODED BY FLI1 FOR TRANSFORMATION
EWING SARCOMA 11-22 TRANSLOCATION PRODUCES A CHIMERIC TRANSCRIPTION FACTOR THAT REQUIRES THE DNA-BINDING DOMAIN ENCODED BY FLI1 FOR TRANSFORMATION
复制标题
DOI：
10.1073/pnas.90.12.5752
复制
发表时间：
1993-06-15
影响因子：
11.1
通讯作者：
DENNY, CT
中科院分区：
文献类型：
--
作者：
MAY, WA;GISHIZKY, ML;DENNY, CT
Ewing肉瘤和原始神经外胚层肿瘤的11；22染色体易位导致了一个嵌合分子，该分子融合了EWS基因的氨基端编码部分和由FLI1基因编码的羧基末端DNA结合域。我们已经分离到第四个EWS-FLI1融合cDNA，它在结构上与前面描述的三种形式不同。为了确定该基因的转化活性，将不同形式的EWS-FLI1融合基因导入NIH3T3细胞。表达1型和4型融合基因的细胞在培养中形成病灶，在软琼脂中形成集落，表明EWS-FLI1是一个转化基因。创建了EWS-FLI1缺失突变体，以在功能上定位嵌合体内的关键区。EWS结构域或与DNA结合结构域对应的FLI1的缺失完全取消了EWS-FLI1转化3T3细胞的能力。这些数据表明，11；22易位的致癌作用是由嵌合转录因子的形成引起的。嵌合转录因子的形成现在已被证明促进神经外胚层和造血细胞来源的肿瘤，这表明这可能是人类致癌的常见机制。
The 11;22 chromosomal translocation specifically linked to Ewing sarcoma and primitive neuroectodermal tumor results in a chimeric molecule fusing the amino-terminal-encoding portion of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI1 gene. We have isolated a fourth EWS-FLI1 fusion cDNA that is structurally distinct from the three forms previously described. To determine the transforming activity of this gene, alternative forms of the EWS-FLI1 fusion were transduced into NIH 3T3 cells. Cells expressing either type 1 or type 4 fusion construct-formed foci in culture and colonies in soft agar, indicating that EWS-FLI1 is a transforming gene. EWS-FLI1 deletion mutants were created to map functionally the critical regions within the chimera. Deletion of either the EWS domain or the FLI1 corresponding to the DNA-binding domain totally abrogated the ability for EWS-FLI1 to transform 3T3 cells. These data indicate that the oncogenic effect of the 11;22 translocation is caused by the formation of a chimeric transcription factor. Formation of chimeric transcription factors has now been demonstrated to promote tumors of both neuroectodermal and hematopoietic origin, suggesting that this may be a common mechanism in human carcinogenesis.