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4. Correction to: Phenytoin inhibits necroptosis

Author

von Mässenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stéphane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, Anders, Hans Joachim, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, and Linkermann, Andreas

Published
2018
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5. Phenytoin inhibits necroptosis

Author

von Mässenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stéphane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, Anders, Hans Joachim, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, and Linkermann, Andreas

Published
2018
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6. Sibiriline, a new small chemical inhibitor of receptor‐interacting protein kinase 1, prevents immune‐dependent hepatitis

Author

Le Cann, Fabienne, Delehouzé, Claire, Leverrier‐Penna, Sabrina, Filliol, Aveline, Comte, Arnaud, Delalande, Olivier, Desban, Nathalie, Baratte, Blandine, Gallais, Isabelle, Piquet‐Pellorce, Claire, Faurez, Florence, Bonnet, Marion, Mettey, Yvette, Goekjian, Peter, Samson, Michel, Vandenabeele, Peter, Bach, Stéphane, and Dimanche‐Boitrel, Marie‐Thérèse

Published
2017
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7. Tip growth in the brown alga Ectocarpus is controlled by a RHO-GAP-BAR domain protein independently from F-actin organisation

Author

Nehr, Zofia, primary, Chenivesse, Sabine, additional, Billoud, Bernard, additional, Genicot, Sabine, additional, Desban, Nathalie, additional, Theodorou, Ioannis, additional, Nasir, Adeel, additional, Le Bail, Aude, additional, Rabillé, Hervé, additional, Godfroy, Olivier, additional, Katsaros, Christos, additional, and Charrier, Bénédicte, additional

Published
2021
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9. Cell cycle-independent furrowing triggered by phosphomimetic mutations of the INCENP STD motif requires Plk1

Author

Papini, Diana, Fant, Xavier, Ogawa, Hiromi, Desban, Nathalie, Samejima, Kumiko, Feizbakhsh, Omid, Askin, Bilge, Ly, Tony, Earnshaw, William C., Ruchaud, Sandrine, Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Phophorylation de protéines et Pathologies Humaines (P3H), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Wellcome Trust Centre for Cell Biology, Station biologique de Roscoff (SBR), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
rho-Associated Kinases, INCENP, Chromosomal Proteins, Non-Histone, [SDV]Life Sciences [q-bio], Cell Cycle, Mitosis, Cell Cycle Proteins, CPC, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], macromolecular substances, Protein Serine-Threonine Kinases, Microtubules, Chromosomes, Furrow initiation, Plk1, Proto-Oncogene Proteins, Mutation, Humans, [CHIM]Chemical Sciences, Aurora B, ComputingMilieux_MISCELLANEOUS, Research Article, Cytokinesis
Abstract

Timely and precise control of Aurora B kinase, the chromosomal passenger complex (CPC) catalytic subunit, is essential for accurate chromosome segregation and cytokinesis. Post-translational modifications of CPC subunits are directly involved in controlling Aurora B activity. Here, we identified a highly conserved acidic STD-rich motif of INCENP that is phosphorylated during mitosis in vivo and by Plk1 in vitro and is involved in controlling Aurora B activity. By using an INCENP conditional-knockout cell line, we show that impairing the phosphorylation status of this region disrupts chromosome congression and induces cytokinesis failure. In contrast, mimicking constitutive phosphorylation not only rescues cytokinesis but also induces ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner independent of cell cycle and microtubule status. Our experiments identify the phospho-regulation of the INCENP STD motif as a novel mechanism that is key for chromosome alignment and cytokinesis. This article has an associated First Person interview with the first author of the paper., Highlighted Article: Phospho-regulation of the INCENP STD motif acts as a novel switch that is key to Aurora B activity modulation, chromosome alignment and cytokinesis.

Published
2019
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10. Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation

Author

Elie, Jonathan, primary, Feizbakhsh, Omid, additional, Desban, Nathalie, additional, Josselin, Béatrice, additional, Baratte, Blandine, additional, Bescond, Amandine, additional, Duez, Julien, additional, Fant, Xavier, additional, Bach, Stéphane, additional, Marie, Dominique, additional, Place, Matthieu, additional, Ben Salah, Sami, additional, Chartier, Agnes, additional, Berteina-Raboin, Sabine, additional, Chaikuad, Apirat, additional, Knapp, Stefan, additional, Carles, Fabrice, additional, Bonnet, Pascal, additional, Buron, Frédéric, additional, Routier, Sylvain, additional, and Ruchaud, Sandrine, additional

Published
2020
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12. Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8

Author

Billot, Katy, primary, Coquil, Charlène, additional, Villiers, Benoit, additional, Josselin-Foll, Béatrice, additional, Desban, Nathalie, additional, Delehouzé, Claire, additional, Oumata, Nassima, additional, Le Meur, Yannick, additional, Boletta, Alessandra, additional, Weimbs, Thomas, additional, Grosch, Melanie, additional, Witzgall, Ralph, additional, Saunier, Sophie, additional, Fischer, Evelyne, additional, Pontoglio, Marco, additional, Fautrel, Alain, additional, Mrug, Michal, additional, Wallace, Darren, additional, Tran, Pamela V., additional, Trudel, Marie, additional, Bukanov, Nikolay, additional, Ibraghimov-Beskrovnaya, Oxana, additional, and Meijer, Laurent, additional

Published
2018
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13. Phenytoin inhibits necroptosis

Author

von Maessenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stephane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, Anders, Hans Joachim, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, Linkermann, Andreas, von Maessenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stephane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, Anders, Hans Joachim, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, and Linkermann, Andreas

Abstract

Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia-reperfusion injury (IRI) and from TNF alpha-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury. In both models, MLKL-ko mice were significantly protected from injury to a degree that was slightly, but statistically significantly exceeding that of RIPK3-deficient mice. We also demonstrated, for the first time, accumulation of pMLKL in the necrotic tubules of human patients with acute kidney injury. However, our data also uncovered unexpected elevation of blood flow in MLKL-ko animals, which may be relevant to IRI and should be considered in the future. To further understand the mode of regulation of cell death by MLKL, we screened a panel of clinical plasma membrane channel blockers and we found phenytoin to inhibit necroptosis. However, we further found that phenytoin attenuated RIPK1 kinase activity in vitro, likely due to the hydantoin scaffold also present in necrostatin-1, and blocked upstream necrosome formation steps in the cells undergoing necroptosis. We further report that this clinically used anticonvulsant drug displayed protection from kidney IRI and TNF alpha-induces SIRS in vivo. Overall, our data reveal the relevance of RIPK3-pMLKL regulation for acute kidney injury and identifies an FDA-approved drug that may be useful for immediate clinical evaluation of inhibition of pro-death RIPK1/RIPK3 activities in human diseases.

Published
2018

14. Phenytoin inhibits necroptosis (vol 9, 359, 2018)

Author

von Maessenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stephane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, JoachimAnders, Hans, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, Linkermann, Andreas, von Maessenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich, Baratte, Blandine, Desban, Nathalie, Bach, Stephane, Schiessl, Ina Maria, Nogusa, Shoko, Balachandran, Siddharth, JoachimAnders, Hans, Ting, Adrian T., Bleich, Markus, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian, and Linkermann, Andreas

Published
2018

15. Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8.

Author

Billot, Katy, Coquil, Charlène, Villiers, Benoit, Josselin-Foll, Béatrice, Desban, Nathalie, Delehouzé, Claire, Oumata, Nassima, Yannick Le Meur, Boletta, Alessandra, Weimbs, Thomas, Grosch, Melanie, Witzgall, Ralph, Saunier, Sophie, Fischer, Evelyne, Pontoglio, Marco, Fautrel, Alain, Mrug, Michal, Wallace, Darren, Tran, Pamela V., and Trudel, Marie

Abstract

Following the discovery of (R)-roscovitine’s beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)- CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1 isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1 are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1 may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates [ABSTRACT FROM AUTHOR]

Published
2018
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16. The Toll-Like Receptor Agonist Imiquimod Is Active against Prions

Author

Oumata, Nassima, Nguyen, Phu Hai, Béringue, Vincent, Soubigou, Flavie, Pang, Yanhong, Desban, Nathalie, Massacrier, Catherine, Morel, Yannis, Paturel, Carine, Contesse, Marie-Astrid, Bouaziz, Serge, Sanyal, Suparna, Galons, Hervé, Blondel, Marc, Voisset, Cécile, Baskakov, Ilia v, Bouaziz, Serge, ManRos Therapeutics, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Innate Pharma, Recherche & Développement, Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Uppsala University, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Protein Folding, Medicin och hälsovetenskap, PrPSc Proteins, MESH: Membrane Glycoproteins, Drug Evaluation, Preclinical, lcsh:Medicine, MESH: Guanosine, Medical and Health Sciences, drugs, Prion Diseases, Mice, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH: Saccharomyces cerevisiae Proteins, yeast based assay, Naturvetenskap, protein folding activity, MESH: Aminoquinolines, neurodegenerative diseases, MESH: Animals, lcsh:Science, 0303 health sciences, Toll-like receptor, Multidisciplinary, Imiquimod, Membrane Glycoproteins, Guanosine, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: PrPSc Proteins, Imidazoles, MESH: Saccharomyces cerevisiae, MESH: Toll-Like Receptor 8, MESH: Toll-Like Receptor 7, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], in vivo, Biochemistry, Aminoquinolines, MESH: Drug Evaluation, Preclinical, 23s ribosomal rna, screening assay, Natural Sciences, MESH: Imidazoles, MESH: Peptide Termination Factors, Peptide Termination Factors, Research Article, Agonist, Saccharomyces cerevisiae Proteins, récepteur de type toll like, medicine.drug_class, Prions, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Protein Folding, 5 percent cream, MESH: Imiquimod, Saccharomyces cerevisiae, Biology, Cell Line, prion, 03 medical and health sciences, Structure-Activity Relationship, MESH: Prions, In vivo, scrapie agent, medicine, Structure–activity relationship, Animals, Humans, mammalian prions, MESH: Mice, 030304 developmental biology, Glutathione Peroxidase, MESH: Humans, lcsh:R, MESH: Prion Diseases, TLR7, In vitro, MESH: Cell Line, Toll-Like Receptor 7, Toll-Like Receptor 8, MESH: Glutathione Peroxidase, lcsh:Q, 030217 neurology & neurosurgery, Ex vivo
Abstract

International audience; Using a yeast-based assay, a previously unsuspected antiprion activity was found for imiquimod (IQ), a potent Toll-like receptor 7 (TLR7) agonist already used for clinical applications. The antiprion activity of IQ was first detected against yeast prions [PSI (+) ] and [URE3], and then against mammalian prion both ex vivo in a cell-based assay and in vivo in a transgenic mouse model for prion diseases. In order to facilitate structure-activity relationship studies, we conducted a new synthetic pathway which provides a more efficient means of producing new IQ chemical derivatives, the activity of which was tested against both yeast and mammalian prions. The comparable antiprion activity of IQ and its chemical derivatives in the above life forms further emphasizes the conservation of prion controlling mechanisms throughout evolution. Interestingly, this study also demonstrated that the antiprion activity of IQ and IQ-derived compounds is independent from their ability to stimulate TLRs. Furthermore, we found that IQ and its active chemical derivatives inhibit the protein folding activity of the ribosome (PFAR) in vitro.

Published
2013
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17. Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Author

Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, Blondel, Marc, Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, and Blondel, Marc

Abstract

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

Published
2010

18. Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

Author

Tribouillard-Tanvier, Deborah, Dos Reis, Suzana, Gug, Fabienne, Voisset, Cecile, Beringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stephane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chedin, Stephane, Vilette, Didier, Galons, Herve, Sanyal, Suparna, Blondel, Marc, Tribouillard-Tanvier, Deborah, Dos Reis, Suzana, Gug, Fabienne, Voisset, Cecile, Beringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stephane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chedin, Stephane, Vilette, Didier, Galons, Herve, Sanyal, Suparna, and Blondel, Marc

Abstract

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases. Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome. Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

Published
2008
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20. Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

Author

Tribouillard-Tanvier, Déborah, primary, Dos Reis, Suzana, additional, Gug, Fabienne, additional, Voisset, Cécile, additional, Béringue, Vincent, additional, Sabate, Raimon, additional, Kikovska, Ema, additional, Talarek, Nicolas, additional, Bach, Stéphane, additional, Huang, Chenhui, additional, Desban, Nathalie, additional, Saupe, Sven J., additional, Supattapone, Surachai, additional, Thuret, Jean-Yves, additional, Chédin, Stéphane, additional, Vilette, Didier, additional, Galons, Hervé, additional, Sanyal, Suparna, additional, and Blondel, Marc, additional

Published
2008
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23. Using budding yeast to screen for anti-prion drugs

Author

Tribouillard, Déborah, primary, Bach, Stéphane, additional, Gug, Fabienne, additional, Desban, Nathalie, additional, Beringue, Vincent, additional, Andrieu, Thibault, additional, Dormont, Dominique, additional, Galons, Hervé, additional, Laude, Hubert, additional, Vilette, Didier, additional, and Blondel, Marc, additional

Published
2006
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28. Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Author

Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, Blondel, Marc, Tribouillard-Tanvier, Déborah, Reis, Suzana Dos, Gug, Fabienne, Voisset, Cécile, Béringue, Vincent, Sabate, Raimon, Kikovska, Ema, Talarek, Nicolas, Bach, Stéphane, Huang, Chenhui, Desban, Nathalie, Saupe, Sven J., Supattapone, Surachai, Thuret, Jean-Yves, Chédin, Stéphane, Vilette, Didier, Galons, Hervé, Sanyal, Suparna, and Blondel, Marc

Abstract

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

29. Cell cycle-independent furrowing triggered by phosphomimetic mutations of the INCENP STD motif requires Plk1.

Author

Papini D, Fant X, Ogawa H, Desban N, Samejima K, Feizbakhsh O, Askin B, Ly T, Earnshaw WC, and Ruchaud S

Subjects
Chromosomal Proteins, Non-Histone metabolism, Chromosomes metabolism, Cytokinesis physiology, Humans, Mitosis physiology, rho-Associated Kinases metabolism, Polo-Like Kinase 1, Cell Cycle physiology, Cell Cycle Proteins metabolism, Microtubules metabolism, Mutation genetics, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism
Abstract

Timely and precise control of Aurora B kinase, the chromosomal passenger complex (CPC) catalytic subunit, is essential for accurate chromosome segregation and cytokinesis. Post-translational modifications of CPC subunits are directly involved in controlling Aurora B activity. Here, we identified a highly conserved acidic STD-rich motif of INCENP that is phosphorylated during mitosis in vivo and by Plk1 in vitro and is involved in controlling Aurora B activity. By using an INCENP conditional-knockout cell line, we show that impairing the phosphorylation status of this region disrupts chromosome congression and induces cytokinesis failure. In contrast, mimicking constitutive phosphorylation not only rescues cytokinesis but also induces ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner independent of cell cycle and microtubule status. Our experiments identify the phospho-regulation of the INCENP STD motif as a novel mechanism that is key for chromosome alignment and cytokinesis.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Published
2019
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30. alpha1beta1-integrin engagement to distinct laminin-1 domains orchestrates spreading, migration and survival of neural crest cells through independent signaling pathways.

Author

Desban N, Lissitzky JC, Rousselle P, and Duband JL

Subjects
Animals, Cell Adhesion physiology, Cell Shape, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Focal Adhesion Protein-Tyrosine Kinases metabolism, Laminin chemistry, Pancreatic Elastase metabolism, Peptide Fragments metabolism, Protein Isoforms chemistry, Protein Isoforms metabolism, Protein Structure, Tertiary, Cell Movement physiology, Cell Survival, Integrin alpha1beta1 metabolism, Laminin metabolism, Neural Crest cytology, Signal Transduction physiology
Abstract

Integrin engagement regulates cell adhesion, shape, migration, growth, and differentiation, but molecular mechanisms coordinating these functions in cells remain unclear. Because of their migratory and differentiation potential, neural crest cells constitute a powerful paradigm to address this question. Here, we describe that laminin-1, a major component of their migration routes, promotes crest cell spreading, migration and survival through two distinct integrin-binding domains that are situated on both sides of its alpha1 subunit and can be separated in the LN-1 elastase proteolytic fragments E1' and E8. Interaction with either domain was mediated by the same integrin alpha1beta1 but produced distinct, complementary responses through specific signaling cascades. FAK activation upon E8 binding induced spreading, formation of actin bundles and focal adhesions, stimulated oriented migration, but failed to support survival. Conversely, Erk activation upon E1' binding promoted long-term survival and random migration without actin reorganization. Consistent with this, interaction with laminin-5 or laminin-10/11, which do not harbor integrin-binding domains in the N-terminal side of their alpha chains, failed to support survival. Thus, the signaling activity and function of integrins might depend on binding domains in their ligands, thereby revealing ligand control of integrin function as a possible mechanism for the modulation and coordination of cell response to adhesive signals.

Published
2006
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31. Cellular localization and signaling activity of beta-catenin in migrating neural crest cells.

Author

de Melker AA, Desban N, and Duband JL

Subjects
Actins metabolism, Active Transport, Cell Nucleus, Animals, Cattle, Cell Adhesion, Cell Communication, Cell Death, Cell Differentiation, Cell Movement, Cell Nucleus metabolism, Cell Proliferation, Chick Embryo, Cytoskeletal Proteins biosynthesis, Cytoskeleton metabolism, Gene Expression Regulation, Developmental, Immunohistochemistry, Immunoprecipitation, In Situ Hybridization, Intercellular Signaling Peptides and Proteins metabolism, Lithium Chloride pharmacology, Mice, Microscopy, Fluorescence, Models, Biological, Neurons metabolism, Quail, Signal Transduction, Time Factors, Trans-Activators biosynthesis, Trypsin pharmacology, Up-Regulation, Wnt Proteins, Wnt1 Protein, beta Catenin, Cytoskeletal Proteins metabolism, Neural Crest cytology, Neural Crest embryology, Trans-Activators metabolism
Abstract

In the vertebrate embryo, development of the neural crest is accompanied by sequential changes in cellular adhesiveness, allowing cells to delaminate from the neural epithelium, to undergo migration through extracellular matrix material, and to coalesce into ganglia of the peripheral nervous system. Because of its dual role in cell adhesion, as a link between cadherins and the actin cytoskeleton, and in cell signaling, as a key mediator of the Wnt-signaling pathway, beta-catenin is a good candidate to play a central role in the control of neural crest cell development. In the present study, we analyzed, by using an in vitro culture system, whether the cellular localization and the signaling activity of beta-catenin are regulated in conjunction with cell migration during ontogeny of trunk neural crest cells in the avian embryo. beta-Catenin molecules were found primarily in association with N-cadherin in the regions of intercellular contacts in most migrating neural crest cells, and only early-migrating cells situated in proximity with the dorsal side of the neural tube showed detectable beta-catenin in their nuclei. This finding indicates that beta-catenin may be recruited for signaling in neural crest cells only transiently at the onset of migration and that sustained beta-catenin signals are not necessary for the progression of migration. The nuclear distribution of beta-catenin within crest cells was not affected upon modification of the N-cadherin-mediated cell-cell contacts, revealing that recruitment of beta-catenin for signaling is not driven by changes in intercellular cohesion during migration. Overstimulation of beta-catenin signals in neural crest cells at the time of their migration, using LiCl treatment or coculture with Wnt-1-producing cells, induced nuclear translocation of beta-catenin and Lef-1 up-regulation in neural crest cells and provoked a marked inhibition of cell delamination and migration. The effect of LiCl and exogenous Wnt-1 on neural crest cells could be essentially attributed to a dramatic decrease in integrin-mediated cell-matrix adhesion as well as a massive reduction of cell proliferation. In addition, although it apparently did not affect expression of neural crest markers, Wnt-1 exposure dramatically affected signaling events involving Notch-Delta, presumably also accounting for the strong reduction in cell delamination. In conclusion, our data indicate that beta-catenin functions primarily in cell adhesion events during migration and may be recruited transiently for signaling during delamination possibly to regulate the balance between cell proliferation and cell differentiation., (Copyright 2004 Wiley-Liss, Inc.)

Published
2004
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