THE EWINGS-SARCOMA EWS/FLI-1 FUSION GENE ENCODES A MORE POTENT TRANSCRIPTIONAL ACTIVATOR AND IS A MORE POWERFUL TRANSFORMING GENE THAN FLI-1

被引:429
|
作者
MAY, WA
LESSNICK, SL
BRAUN, BS
KLEMSZ, M
LEWIS, BC
LUNSFORD, LB
HROMAS, R
DENNY, CT
机构
[1] UNIV CALIF LOS ANGELES,DEPT PEDIAT,DIV HEMATOL ONCOL,GWYNNE HAZEN CHERRY MEM LABS,LOS ANGELES,CA 90024
[2] UNIV CALIF LOS ANGELES,SCH MED,JONSSON COMPREHENS CANC CTR,LOS ANGELES,CA 90024
[3] UNIV CALIF LOS ANGELES,INST MOLEC BIOL,LOS ANGELES,CA 90024
[4] INDIANA UNIV,MED CTR,DEPT MICROBIOL & IMMUNOL,INDIANAPOLIS,IN 46202
[5] INDIANA UNIV,MED CTR,DIV HEMATOL ONCOL,INDIANAPOLIS,IN 46202
[6] INDIANA UNIV,MED CTR,WALTHER ONCOL CTR,INDIANAPOLIS,IN 46202
关键词
D O I
10.1128/MCB.13.12.7393
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-1 has been shown to be a potent transforming gene, suggesting that it plays an important role in the genesis of these human tumors. We now demonstrate that EWS/FLI-1 has the characteristics of an aberrant transcription factor. Subcellular fractionation experiments localized the EWS/FLI-1 protein to the nucleus of primitive neuroectodermal tumor cells. EWS/FLI-1 specifically bound in vitro an ets-2 consensus sequence similarly to normal FLI-1. When coupled to a GAL4 DNA-binding domain, the amino-terminal EWS/FLI-1 region was a much more potent transcriptional activator than the corresponding amino-terminal domain of FLI-1. Finally, EWS/FLI-1 efficiently transformed NIH 3T3 cells, but FLI-1 did not. These data suggest that EWS/FLI-1, functioning as a transcription factor, leads to a phenotype dramatically different from that of cells expressing FLI-1. EWS/FLI-1 could disrupt normal growth and differentiation either by more efficiently activating FLI-1 target genes or by inappropriately modulating genes normally not responsive to FLI-1.
引用
收藏
页码:7393 / 7398
页数:6
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