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Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene.
Oncogene. 1995 Feb 02; 10(3):423-31.O

Abstract

The (11;22) chromosomal translocation found in Ewing's sarcoma and related tumors fuses the amino terminus of the EWS protein to the DNA-binding domain of the FLI-1 transcription factor. In contrast to normal FLI-1, the EWS/FLI-1 fusion transforms NIH3T3 cells and this activity requires both EWS and FLI-1 sequences. Reporter gene assays showed that the portion of EWS fused to FLI-1 encodes a strong transcriptional activation domain. To determine whether this function is necessary for transformation by EWS/FLI-1, deletion analysis of EWS was performed. We found that the EWS domain could be functionally subdivided into two regions: (i) an amino terminal domain (domain A) which transforms efficiently when fused to FLI-1 but has little transactivation activity in a model system and (ii) a distal region (domain B) which transactivates efficiently but transforms less efficiently when fused to FLI-1. Replacement of the EWS domain with known heterologous transcriptional activation domains yielded chimeric FLI-1 fusions that in some instances could transform NIH3T3 cells. Finally we demonstrate that EWS/FLI-1 and related FLI-1 chimeras are able to cooperate with another transcription factor to activate a model reporter gene. These results further demonstrate that EWS/FLI-1 is an aberrant transcription factor and suggest that the EWS domain mediates important protein-protein interactions with other factors resulting in the transcriptional modulation of target genes.

Authors+Show Affiliations

Molecular Biology Institute, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles 90024.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

7845667

Citation

Lessnick, S L., et al. "Multiple Domains Mediate Transformation By the Ewing's Sarcoma EWS/FLI-1 Fusion Gene." Oncogene, vol. 10, no. 3, 1995, pp. 423-31.
Lessnick SL, Braun BS, Denny CT, et al. Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. Oncogene. 1995;10(3):423-31.
Lessnick, S. L., Braun, B. S., Denny, C. T., & May, W. A. (1995). Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. Oncogene, 10(3), 423-31.
Lessnick SL, et al. Multiple Domains Mediate Transformation By the Ewing's Sarcoma EWS/FLI-1 Fusion Gene. Oncogene. 1995 Feb 2;10(3):423-31. PubMed PMID: 7845667.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. AU - Lessnick,S L, AU - Braun,B S, AU - Denny,C T, AU - May,W A, PY - 1995/2/2/pubmed PY - 1995/2/2/medline PY - 1995/2/2/entrez SP - 423 EP - 31 JF - Oncogene JO - Oncogene VL - 10 IS - 3 N2 - The (11;22) chromosomal translocation found in Ewing's sarcoma and related tumors fuses the amino terminus of the EWS protein to the DNA-binding domain of the FLI-1 transcription factor. In contrast to normal FLI-1, the EWS/FLI-1 fusion transforms NIH3T3 cells and this activity requires both EWS and FLI-1 sequences. Reporter gene assays showed that the portion of EWS fused to FLI-1 encodes a strong transcriptional activation domain. To determine whether this function is necessary for transformation by EWS/FLI-1, deletion analysis of EWS was performed. We found that the EWS domain could be functionally subdivided into two regions: (i) an amino terminal domain (domain A) which transforms efficiently when fused to FLI-1 but has little transactivation activity in a model system and (ii) a distal region (domain B) which transactivates efficiently but transforms less efficiently when fused to FLI-1. Replacement of the EWS domain with known heterologous transcriptional activation domains yielded chimeric FLI-1 fusions that in some instances could transform NIH3T3 cells. Finally we demonstrate that EWS/FLI-1 and related FLI-1 chimeras are able to cooperate with another transcription factor to activate a model reporter gene. These results further demonstrate that EWS/FLI-1 is an aberrant transcription factor and suggest that the EWS domain mediates important protein-protein interactions with other factors resulting in the transcriptional modulation of target genes. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/7845667/Multiple_domains_mediate_transformation_by_the_Ewing's_sarcoma_EWS/FLI_1_fusion_gene_ L2 - https://www.lens.org/lens/search/patent/list?q=citation_id:7845667 DB - PRIME DP - Unbound Medicine ER -