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Your search keyword '"European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015)"' showing total 5 results
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5 results on '"European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015)"'

1. GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1

Author

Almada, Luciana L., Barroso, Kim, Sen, Sandhya, Törüner, Murat, Sigafoos, Ashley N, Raja Arul, Glancis L, Pease, David R, Vera, Renzo E., Olson, Rachel L O, Auner, Holger W, Pedeux, Rémy, Iovanna, Juan L, Chevet, Eric, Fernandez-Zapico, Martin E, Mayo Clinic [Rochester], Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Imperial College London, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was funded by grants from INSERM, Institut National du Cancer (INCa, PLBio 2017, 2019, 2020), Région Bretagne, Rennes Métropole, Fondation pour la recherche Médicale (FRM, DEQ20180339169), EU H2020 MSCA ITN-675448 (TRAINERS), la Ligue Contre le Cancer Comités d'Ille-et-Vilaine, des Côtes d'Armor et du Morbihan and MSCA RISE-734749 (INSPIRED) to EC and MEFZ was supported by NCI CA136526. KB was funded by a grant from la Ligue Contre le Cancer., and European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015)

Subjects
Structural Biology, p97/VCP, GLI1, Genetics, Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, UPR, USF2, ER stress, Molecular Biology, Biochemistry, HDAC1, Hedgehog
Abstract

International audience; Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.

Published
2023
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2. Stress-induced tyrosine phosphorylation of RtcB modulates IRE1 activity and signaling outputs

Author

Alexandra Papaioannou, Federica Centonze, Alice Metais, Marion Maurel, Luc Negroni, Matías Gonzalez-Quiroz, Sayyed Jalil Mahdizadeh, Gabriella Svensson, Ensieh Zare, Alice Blondel, Albert C Koong, Claudio Hetz, Rémy Pedeux, Michel L Tremblay, Leif A Eriksson, Eric Chevet, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Gothenburg (GU), The University of Texas M.D. Anderson Cancer Center [Houston], Universidad de Chile = University of Chile [Santiago] (UCHILE), McGill University = Université McGill [Montréal, Canada], This work was funded by grants from Institut National du Cancer (PLBIO), SIRIC-ILIAD/Cancéropôle Grand Ouest to E Chevet, Fondation pour la Recherche Médicale (équipe labellisée 2018) to E Chevet and R Pedeux, by European Union (EU) H2020 MSCA ITN-675448 (TRAINERS), and MSCA RISE-734749 (INSPIRED) grants to E Chevet and LA Eriksson. The Swedish Research Council (VR) and the Swedish National Infrastructure for Computing are gratefully acknowledged for funding and allocations of computing time at the C3SE and PDC supercomputing centers, respectively (LA Eriksson). A Papaioannou is a Marie Curie early-stage researcher funded by EU H2020 MSCA ITN-675448 (TRAINERS). A Metais was funded by the Fondation ARC pour la recherche contre le cancer. SJ Mahdizadeh was funded by the Vinnova Seal-of-Excellence programme 2019-02205 (CaTheDRA)., and European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015)

Subjects
X-Box Binding Protein 1, Ribonucleases, Ecology, Health, Toxicology and Mutagenesis, Endoribonucleases, Tyrosine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Plant Science, RNA, Messenger, Phosphorylation, Protein Serine-Threonine Kinases, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract

International audience; ER stress is mediated by three sensors and the most evolutionary conserved IRE1α signals through its cytosolic kinase and endoribonuclease (RNase) activities. IRE1α RNase activity can either catalyze the initial step of XBP1 mRNA unconventional splicing or degrade a number of RNAs through regulated IRE1-dependent decay. Until now, the biochemical and biological outputs of IRE1α RNase activity have been well documented; however, the precise mechanisms controlling whether IRE1α signaling is adaptive or pro-death (terminal) remain unclear. We investigated those mechanisms and hypothesized that XBP1 mRNA splicing and regulated IRE1-dependent decay activity could be co-regulated by the IRE1α RNase regulatory network. We identified that RtcB, the tRNA ligase responsible for XBP1 mRNA splicing, is tyrosine-phosphorylated by c-Abl and dephosphorylated by PTP1B. Moreover, we show that the phosphorylation of RtcB at Y306 perturbs RtcB interaction with IRE1α, thereby attenuating XBP1 mRNA splicing. Our results demonstrate that the IRE1α RNase regulatory network is dynamically fine-tuned by tyrosine kinases and phosphatases upon various stresses and that the extent of RtcB tyrosine phosphorylation determines cell adaptive or death outputs.

Published
2022
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3. Structural and molecular bases to IRE1 activity modulation

Author

Nicolas Gouault, Timothy Langlais, Xavier Guillory, Eric Chevet, François Carreaux, Diana Pelizzari-Raymundo, Leif A. Eriksson, Sayyed Jalil Mahdizadeh, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Gothenburg (GU), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Fondation pour la Recherche Medicale (FRM) Fondation pour la Recherche Medicale [DEQ20180339169], ERANET, Agence Nationale de la Recherche (ERAAT) French National Research Agency (ANR), EU European Commission [H2020 MSCA ITN-675448, MSCA RISE-734749], Swedish Research Council (VR) Swedish Research Council [2019-3684], Vinnova Seal-of-Excellence programVinnova [2019-02205], Ecole Doctorale 3M, university of Rennes 1, Region BretagneRegion Bretagne, Fondation ARC pour la recherche sur le cancerFondation ARC pour la Recherche sur le Cancer [PDF20191209830], Vinnova Seal-of-Excellence program Vinnova [2019-02205], Region Bretagne Region Bretagne, Fondation ARC pour la recherche sur le cancer Fondation ARC pour la Recherche sur le Cancer [PDF20191209830], European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), European Project: 777657,H2020-EU.1.3.3. - Stimulating innovation by means of cross-fertilisation of knowledge,777657,MSCA-RISE(2018), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CRLCC Eugène Marquis (CRLCC)

Subjects
Protein Folding, RNase P, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, IRE1, Protein Serine-Threonine Kinases, Endoplasmic Reticulum, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endoribonucleases, Animals, Homeostasis, Humans, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, Molecular Biology, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Kinase, Chemistry, Endoplasmic reticulum, structure activity relationship (SAR), Cell Biology, unfolded protein response, Endoplasmic Reticulum Stress, Transmembrane protein, Cell biology, Cytosol, structure-based drug design (SBDD), 030220 oncology & carcinogenesis, Unfolded protein response, Protein folding, ER stress, Signal Transduction
Abstract

International audience; The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

Published
2021
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4. When Endoplasmic Reticulum Proteostasis Meets the DNA Damage Response

Author

Alice Blondel, Matías González-Quiroz, Rémy Pedeux, Alfredo Sagredo, Eric Chevet, Claudio Hetz, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Chile = University of Chile [Santiago] (UCHILE), CRLCC Eugène Marquis (CRLCC), Institute of Catalysis and Petroleum Chemistry, Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) fellowship (PCHA/Doctorado Nacional/2016-21160232), Chile, (to M.G-Q.), doctoral fellowship from the Association pour les Recommendations en Dermatologie (ARED)/INSERM Région Bretagne, France, (to A.B.), the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 3190738 and Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP) GERO-15150012, Chile, (to A.S.), FONDAP program Nº 15150012, Millennium Institute P09-015-F, Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDEF) ID16I10223 and D11E1007, and FONDECYT-T1180186 and Ecos-CONICYT C17S02, Chile, (to C.H.), the Institut National du Cancer (INCa PLBIO), Agence Nationale de la Recherche (ANR) in the framework of European Research Area Network ERAAT, and EU Horizon 2020 Marie Skłodowska-Curie Action (MSCA) ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED), France, (to E.C.), and the Fondation pour la Recherche Médicale (FMR, DEQ20180339169), Ligue Contre le Cancer Grand Ouest, and INSERM, France, (to R.P.)., European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
PERK, DNA damage, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, DNA damage response, Models, Biological, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, proteostasis, Endoplasmic reticulum, Cell Biology, IRE1α, unfolded protein response, 3. Good health, Cell biology, body regions, Crosstalk (biology), Proteostasis, Apoptosis, ATM, Proteome, biological sciences, Unfolded protein response, Signal transduction, 030217 neurology & neurosurgery, DNA Damage, Signal Transduction
Abstract

International audience; Sustaining both proteome and genome integrity (GI) requires the integration of a wide range of mechanisms and signaling pathways. These comprise, in particular, the unfolded protein response (UPR) and the DNA damage response (DDR). These adaptive mechanisms take place respectively in the endoplasmic reticulum (ER) and in the nucleus. UPR and DDR alterations are associated with aging and with pathologies such as degenerative diseases, metabolic and inflammatory disorders, and cancer. We discuss the emerging signaling crosstalk between UPR stress sensors and the DDR, as well as their involvement in cancer biology.

Published
2020
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5. Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo

Author

Qingping Zeng, Raphael Pineau, Pierre-Jean Le Reste, Afshin Samali, Amandine Etcheverry, Adrienne M. Gorman, Juhi Samal, Aristotelis Chatziioannou, Jean Mosser, Nicolas Soriano, Eric Chevet, Marc Aubry, Stéphanie Lhomond, Gwénaële Jégou, John B. Patterson, Tony Avril, Konstantinos Voutetakis, Abhay Pandit, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Rennes Brain Cancer Team (REACT), University of Thessaly [Volos] (UTH), National University of Ireland [Galway] (NUI Galway), Fosun Orinove PharmaTech Inc.[Newbury Park, CA], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), CHU Pontchaillou [Rennes], National Hellenic Research Foundation [Athens], Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was funded by grants from the French National Cancer Institute (INCa, PLBIO2017, 2019, 2020), the Fondation pour la recherche Médicale (FRM, équipe labellisée 2018) to EC and EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) grants to AS, AC and EC. The work was also supported in part by research grant from Science Foundation Ireland (SFI), co-funded under the European Regional Development Fund under Grant number 13/RC/2073., BIOSIT H2P2 platform, BIOSIT Animal facility ARCHE (https://biosit.univ-rennes1.fr/), European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, Disease, Injections, Intralesional, Mice, 0302 clinical medicine, Tumor Microenvironment, 0303 health sciences, Stress sensor, Brain Neoplasms, Combined Modality Therapy, Chemotherapy regimen, Neoadjuvant Therapy, Treatment efficacy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, 030220 oncology & carcinogenesis, Immunocompetence, Craniotomy, medicine.medical_specialty, Morpholines, [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1, 03 medical and health sciences, Animal model, Drug Therapy, In vivo, Cell Line, Tumor, Internal medicine, medicine, Animals, Humans, Benzopyrans, 030304 developmental biology, Chemotherapy, Radiotherapy, business.industry, Gene Expression Profiling, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Unfolded protein response, Unfolded Protein Response, Tumor surgery, business, Glioblastoma, Endoplasmic reticulum
Abstract

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy patient’s survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed a novel immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.

Published
2020
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