Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusion of the 5' half of the Ewing's sarcoma (ES) gene EWS with the DNA-binding domain of several transcription factors has been detected in many human tumors. The t(11;22)(q24;q12) chromosomal translocation is specifically linked to ES and primitive neuroectodermal tumors and results, in the majority of cases, in the fusion of the amino terminus of the EWS gene to the carboxyl-terminal DNA-binding domain of the FLI1 gene. The chimeric protein has been shown to be oncogenic, a potent transcriptional activator, and necessary for the maintenance of the Ewing's phenotype, making it an attractive target for gene therapy. In this study, we demonstrate that the ES transformed phenotype can be suppressed by chimeric transcriptional repressors containing the DNA-binding domain of FLI1 and the regulatory and repressor domain of ERF, a transcription suppressor and member of the ets gene family. The hybrid repressor is expressed at levels comparable with EWS/FLI1, does not affect EWS/FLI1 expression, and exhibits similar DNA-binding specificity but suppresses transcriptional activity. The FLI1/ERF repressor, like the wild-type ERF, is regulated by mitogen-activated protein kinase-dependent subcellular localization. Our data suggest that transformation by EWS/FLI1 may partially be due to activation of specific EWS/FLI1-regulated genes involved in cell proliferation.
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PMID:Suppression of the Ewing's sarcoma phenotype by FLI1/ERF repressor hybrids. 1097 80

In 85% of Ewing family tumors, the NH2 terminus of EWS is fused to the DNA-binding domain of FLI1, an ets transcription factor. The resulting chimeric protein is a strong transcriptional activator with transforming activity. We report that EWS and EWS-FLI1 interact via their common NH2 terminus with the COOH terminus of BARD1, a putative tumor suppressor, in vitro and in vivo. Because BARD1 associates via its NH2-terminal RING domain with the breast cancer susceptibility gene BRCA1 that provides a platform for interactions with proteins involved in DNA repair and checkpoint control, our results provide a link between the Ewing's sarcoma gene product and the genome surveillance complex.
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PMID:Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. 1218 11

Ewing's sarcoma family of tumors (ESFT) affect patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. ESFTs are characterized by a translocation that occurs in 95% of tumors. This translocation joins the Ewing's sarcoma gene (EWS) located on chromosome 22 to an ets family gene; either friend leukemia insertion (FLI)1 located on chromosome 11, t(11;22), or ets-related gene (ERG) located on chromosome 21, t(21;22). The EWS-FLI1 fusion transcript encodes a 68 kDa protein with two primary domains. The EWS domain is a potent transcriptional activator, while the FLI1 domain contains a highly conserved ets DNA binding domain. ESFT presents a clinical challenge, especially in patients with metastatic disease in which dose-intensifying chemotherapy with bone-marrow transplantation does not improve survival. EWS-FLI1 is only present in ESFT cells and does not exist in any normal cell of the body. Experiments using ESFT cell lines or animal xenograft models have proven that EWS-FLI1 is required for tumor survival. Therefore, ESFT contains a unique protein generated by a tumor-specific translocation that has great potential as a molecular target for therapy. However, therapeutic applications directed towards eliminating or inactivating EWS-FLI1 have not reached the clinic. EWS-FLI1 has been a very difficult molecule to directly analyze in vitro due to poor solubility. Recent advances in generating recombinant EWS-FLI1 and novel data on the cellular functions of EWS-FLI1 should enhance progress towards understanding and application.
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PMID:Ewing's sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. 1655 28

Targeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a pathognomonic chromosomal translocation. The EWS-FLI1 fusion protein includes the EWS domain, a potent transcriptional activator alongside the highly conserved FLI1 ets DNA-binding domain. Because of the combination of these domains, the EWS-FLI1 fusion protein acts as an aberrant transcription factor whose expression results in cellular transformation. EWS-FLI1 functions by binding to normal cellular protein partners in transcription and splicing, similar to how a virus would corrupt normal cellular machinery for virion production. Therefore, understanding the protein-protein interactions of EWS-FLI1 and the pathways that are regulated by these partnerships will inform both oncogenesis and therapeutics. This review describes the known protein partners and transcriptional targets of EWS-FLI1, while proposing strategies for exploiting these partnerships with targeted therapy.
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PMID:Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. 2054 96