ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma
| العنوان: | ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma |
|---|---|
| المؤلفون: | Soma Ghosh, Arunachalam Sekar, Andrei Zinovyev, Diana Drago-Garcia, Mattia Lauriola, Ilaria Marrocco, Swati Srivastava, Olivier Delattre, Yuya Haga, Nishanth Belugali Nataraj, Chamutal Bornstein, Ron Rotkopf, Didier Surdez, Yosef Yarden, Heinrich Kovar, Adi Kimchi, Yasuo Tsutsumi, Eyal David, Lee Roth, Donatella Romaniello, Yuval Gilad, Olivier Mirabeau, Ido Amit |
| المساهمون: | Srivastava S., Nataraj N.B., Sekar A., Ghosh S., Bornstein C., Drago-Garcia D., Roth L., Romaniello D., Marrocco I., David E., Gilad Y., Lauriola M., Rotkopf R., Kimchi A., Haga Y., Tsutsumi Y., Mirabeau O., Surdez D., Zinovyev A., Delattre O., Kovar H., Amit I., Yarden Y. |
| المصدر: | Cell Reports Cell Reports, Vol 29, Iss 1, Pp 104-117.e4 (2019) |
| بيانات النشر: | Elsevier B.V., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Chromosomal translocation, Bone Neoplasms, Mice, SCID, Sarcoma, Ewing, protein-fragment complementation assay, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Metastasis, 03 medical and health sciences, Mice, 0302 clinical medicine, Glucocorticoid receptor, Receptors, Glucocorticoid, Protein-fragment complementation assay, Cell Movement, medicine, glucocorticoid receptor, Animals, Humans, metastasis, lcsh:QH301-705.5, Transcription factor, Cell Proliferation, Cell Nucleus, Gene knockdown, Settore BIO/11 - BIOLOGIA MOLECOLARE, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-fli-1, fungi, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, HEK293 Cells, lcsh:Biology (General), FLI1, Cancer research, cancer therapy, metastasi, Female, Sarcoma, RNA-Binding Protein EWS, 030217 neurology & neurosurgery, Ewing sarcoma |
| الوصف: | Summary 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. Graphical Abstract Highlights • Glucocorticoids activate GR, an inducible TF regulating growth and metabolism • Protein complementation assays identified FLI1 and ERG as GR binders and activators • EWS-FLI1, a fusion protein, drives Ewing sarcoma (ES) and binds with activated GR • Pharmacological inhibition of GR activation retards progression in ES animal models The single oncogene of Ewing sarcoma (ES), a childhood cancer, encodes a FLI1 fusion protein. Srivastava et al. report physical interactions between the fusion protein and the glucocorticoid receptor. Drug-induced inhibition of these interactions retards the progression of ES in mouse models. |
| وصف الملف: | STAMPA |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a4803e3e07c757b737dad8793913372aTest https://hdl.handle.net/10807/227209Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a4803e3e07c757b737dad8793913372a |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |