ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma.

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Tytuł:: ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma.
Autorzy:: Srivastava S; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Nataraj NB; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Sekar A; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Ghosh S; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Bornstein C; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Drago-Garcia D; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Roth L; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Romaniello D; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Marrocco I; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
David E; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Gilad Y; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Lauriola M; Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
Rotkopf R; Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
Kimchi A; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Haga Y; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Tsutsumi Y; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Japan.
Mirabeau O; PSL Research University, 'Genetics and Biology of Cancers' Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France.
Surdez D; PSL Research University, 'Genetics and Biology of Cancers' Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France.
Zinovyev A; Institut Curie, PSL Research University, INSERM U900, Mines ParisTech, Paris, France.
Delattre O; PSL Research University, 'Genetics and Biology of Cancers' Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France.
Kovar H; Children's Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung and Department of Pediatrics, Medical University Vienna, Vienna, Austria.
Amit I; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Yarden Y; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: .
Źródło:: Cell reports [Cell Rep] 2019 Oct 01; Vol. 29 (1), pp. 104-117.e4.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: [Cambridge, MA] : Cell Press, c 2012-
MeSH Terms:: Proto-Oncogene Proteins c-ets/*metabolism
Receptors, Glucocorticoid/*metabolism
Sarcoma, Ewing/*metabolism
Animals ; Bone Neoplasms/metabolism ; Cell Movement/physiology ; Cell Nucleus/metabolism ; Cell Proliferation/physiology ; Female ; Gene Expression Regulation, Neoplastic/physiology ; HEK293 Cells ; Humans ; Mice ; Mice, SCID ; Proto-Oncogene Protein c-fli-1/metabolism ; RNA-Binding Protein EWS/metabolism
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Grant Information:: 740469 International ERC_ European Research Council
Contributed Indexing:: Keywords: Ewing sarcoma; cancer therapy; glucocorticoid receptor; metastasis; protein-fragment complementation assay
Substance Nomenclature:: 0 (Proto-Oncogene Protein c-fli-1)
0 (Proto-Oncogene Proteins c-ets)
0 (RNA-Binding Protein EWS)
0 (Receptors, Glucocorticoid)
Entry Date(s):: Date Created: 20191003 Date Completed: 20200917 Latest Revision: 20210924
Update Code:: 20240104
PubMed Central ID:: PMC6899513
DOI:: 10.1016/j.celrep.2019.08.088
PMID:: 31577941
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The glucocorticoid receptor (GR) acts as a ubiquitous cortisol-dependent transcription factor (TF). To identify co-factors, we used protein-fragment complementation assays and found that GR recognizes FLI1 and additional ETS family proteins, TFs relaying proliferation and/or migration signals. Following steroid-dependent translocation of FLI1 and GR to the nucleus, the FLI1-specific domain (FLS) binds with GR and strongly enhances GR's transcriptional activity. This interaction has functional consequences in Ewing sarcoma (ES), childhood and adolescence bone malignancies driven by fusions between EWSR1 and FLI1. In vitro, GR knockdown inhibited the migration and proliferation of ES cells, and in animal models, antagonizing GR (or lowering cortisol) retarded both tumor growth and metastasis from bone to lung. Taken together, our findings offer mechanistic rationale for repurposing GR-targeting drugs for the treatment of patients with ES.
(Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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