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1. A Novel 8-Predictors Signature to Predict Complicated Disease Course in Pediatric-onset Crohn’s Disease: A Population-based Study

Author

Sarter, Hélène, Savoye, Guillaume, Marot, Guillemette, Ley, Delphine, Turck, Dominique, Hugot, Jean-Pierre, Vasseur, Francis, Duhamel, Alain, Wils, Pauline, Princen, Fred, Colombel, Jean-Frédéric, Gower-Rousseau, Corinne, Fumery, Mathurin, Al Hameedi, R, Al Khatib, M, Al Turk, S, Agoute, E, Andre, J, Antonietti, M, Aouakli, A, Armand, A, Armengol-Debeir, L, Aroichane, I, Assi, F, Aubet, J, Auxenfants, E, Avram, A, Ayafi-Ramelot, F, Azzouzi, K, Bankovski, D, Barbry, B, Bardoux, N, Baron, P, Baudet, A, Bayart, P, Bazin, B, Bebahani, A, Becqwort, J, Bellati, S, Benet, V, Benali, H, Benard, C, Benguigui, C, Ben Soussan, E, Bental, A, Berkelmans, I, Bernet, J, Bernou, K, Bernou-Dron, C, Bertot, P, Bertiaux-Vandaële, N, Bertrand, V, Billoud, E, Biron, N, Bismuth, B, Bleuet, M, Blondel, F, Blondin, V, Bobula, M, Bohon, P, Bondjemah, V, Boniface, E, Bonkovski, D, Bonnière, P, Bonvarlet, E, Bonvarlet, P, Boruchowicz, A, Bostvironnois, R, Boualit, M, Bouazza, A, Bouche, B, Boudaillez, C, Bourgeaux, C, Bourgeois, M, Bourguet, A, Bourienne, A, Boutaleb, H, Bouthors, A, Branche, J, Bray, G, Brazier, F, Breban, P, Bridenne, M, Brihier, H, Bril, L, Brung-Lefebvre, V, Bulois, P, Burgiere, P, Butel, J, Canva, J, Canva-Delcambre, V, Capron, J, Cardot, F, Carette, S, Carpentier, P, Cartier, E, Cassar, J, Cassagnou, M, Castex, J, Catala, P, Cattan, S, Catteau, S, Caujolle, B, Cayron, G, Chandelier, C, Chantre, M, Charles, J, Charneau, T, Chavance-Thelu, M, Cheny, A, Chirita, D, Choteau, A, Claerbout, J, Clergue, P, Coevoet, H, Cohen, G, Collet, R, Colin, M, Colombel, J, Coopman, S, Cordiez, L, Corvisart, J, Cortot, A, Couttenier, F, Crinquette, J, Crombe, V, Dadamessi, I, Daoudi, H, Dapvril, V, Davion, T, Dautreme, S, Debas, J, Decoster, S, Degrave, N, Dehont, F, Delatre, C, Delcenserie, R, Delesalle, D, Delette, O, Delgrange, T, Delhoustal, L, Delmotte, J, Demmane, S, Deregnaucourt, G, Descombes, P, Desechalliers, J, Desmet, P, Desreumaux, P, Desseaux, G, Desurmont, P, Devienne, A, Devouge, E, Devred, M, Devroux, A, Dewailly, A, Dharancy, S, Di Fiore, A, Djedir, D, Djedir, R, Doleh, W, Dreher-Duwat, M, Dubois, R, Duburque, C, Ducatillon, P, Duclay, J, Ducrocq, B, Ducrot, F, Ducrotte, P, Dufilho, A, Duhamel, C, Dujardin, D, Dumant-Forest, C, Dupas, J, Dupont, F, Duranton, Y, Duriez, A, Duveau, N, El Achkar, K, El Farisi, M, Elie, C, Elie-Legrand, M, Elkhaki, A, Eoche, M, Essmaeel, E, Evrard, D, Evrard, J, Fatome, A, Filoche, B, Finet, L, Flahaut, M, Flamme, C, Foissey, D, Fournier, P, Foutrein-Comes, M, Foutrein, P, Fremond, D, Frere, T, Gallais, P, Gamblin, C, Ganga, S, Gerard, R, Geslin, G, Gheyssens, Y, Ghossini, N, Ghrib, S, Gilbert, T, Gillet, B, Godart, D, Godard, P, Godchaux, J, Godchaux, R, Goegebeur, G, Goria, O, Gottrand, F, Gower, P, Grandmaison, B, Groux, M, Guedon, C, Guerbeau, L, Gueroult-Dero, M, Guillard, J, Guillem, L, Guillemot, F, Guimberd, D, Haddouche, B, Hakim, S, Hanon, D, Hautefeuille, V, Heckestweiller, P, Hecquet, G, Hedde, J, Hellal, H, Henneresse, P, Heyman, B, Heraud, M, Herve, S, Hochain, P, Houssin-Bailly, L, Houcke, P, Huguenin, B, Iobagiu, S, Istanboli, S, Ivanovic, A, Iwanicki-Caron, I, Janicki, E, Jarry, M, Jeu, J, Joly, J, Jonas, C, Jouvenet, A, Katherin, F, Kerleveo, A, Khachfe, A, Kiriakos, A, Kiriakos, J, Klein, O, Kohut, M, Kornhauser, R, Koutsomanis, D, Laberenne, J, Lacotte, E, Laffineur, G, Lagarde, M, Lalanne, A, Lalieu, A, Lannoy, P, Lapchin, J, Laprand, M, Laude, D, Leblanc, R, Lecieux, P, Lecleire, S, Leclerc, N, Le Couteulx, C, Ledent, J, Lefebvre, J, Lefiliatre, P, Le Goffic, C, Legrand, C, Le Grix, A, Lelong, P, Leluyer, B, Lemaitre, C, Lenaerts, C, Lepeut, G, Lepileur, L, Leplat, A, Lepoutre-Dujardin, E, Leroi, H, Leroy, M, Le Roy, P, Lesage, B, Lesage, J, Lesage, X, Lescanne-Darchis, I, Lescut, J, Lescut, D, Leurent, B, Levy, P, Lhermie, M, Libier, L, Lion, A, Lisambert, B, Loge, I, Loire, F, Loreau, J, Louf, S, Louvet, A, Lubret, L, Luciani, M, Lucidarme, D, Lugand, J, Macaigne, O, Maetz, D, Maillard, D, Mancheron, H, Manolache, O, Marks-Brunel, A, Marre, C, Marti, R, Martin, F, Martin, G, Marzloff, E, Mathurin, P, Mauillon, J, Maunoury, V, Maupas, J, Medam Djomo, M, Mechior, C, Melki, Z, Mesnard, B, Metayer, P, Methari, L, Meurisse, B, Meurisse, F, Michaud, L, Mirmaran, X, Modaine, P, Monthe, A, Morel, L, Mortier, P, Moulin, E, Mouterde, O, Mozziconaci, N, Mudry, J, Nachury, M, Ngo, M, N’guyen Khac, Eric, Notteghem, B, Ollevier, V, Ostyn, A, Ouraghi, A, Oussadou, B, Ouvry, D, Paillot, B, Painchart, C, Panien-Claudot, N, Paoletti, C, Papazian, A, Parent, B, Pariente, B, Paris, J, Patrier, P, Paupard, T, Pauwels, B, Pauwels, M, Penninck, E, Petit, R, Piat, M, Piotte, S, Plane, C, Plouvier, B, Pollet, E, Pommelet, P, Pop, D, Pordes, C, Pouchain, G, Prades, P, Prevost, A, Prevost, J, Quartier, G, Quesnel, B, Queuniet, A, Quinton, J, Rabache, A, Rabelle, P, Raclot, G, Ratajczyk, S, Rault, D, Razemon, V, Reix, N, Renaut-Vantroys, T, Revillion, M, Riachi, G, Richez, C, Robinson, P, Rodriguez, J, Roger, J, Roux, J, Rudelli, A, Saber, A, Savoye, G, Schlossberg, P, Sefrioui, D, Segrestin, M, Seguy, D, Seminur, C, Serin, M, Seryer, A, Sevenet, F, Shekh, N, Silvie, J, Simon, V, Spyckerelle, C, Talbodec, N, Tavernier, N, Tchandeu, H, Techy, A, Thelu, J, Thevenin, A, Thiebault, H, Thomas, J, Thorel, J, Thuillier, C, Tielman, G, Tode, M, Toisin, J, Tonnel, J, Touchais, J, Toumelin, P, Touze, Y, Tranvouez, J, Triplet, C, Triki, N, Turck, D, Uhlen, S, Vaillant, E, Valmage, C, Vanco, D, Vandaele-Bertiaux, N, Vandamme, H, Vanderbecq, E, Vander Eecken, E, Vandermolen, P, Vandevenne, P, Vandeville, L, Vandewalle, A, Vandewalle, C, Vaneslander, P, Vanhoove, J, Vanrenterghem, A, Vanveuren, C, Varlet, P, Vasies, I, Verbiese, G, Verlynde, J, Vernier-Massouille, G, Vermelle, P, Verne, C, Vezilier-Cocq, P, Vigneron, B, Vincendet, M, Viot, J, Voiment, Y, Wacrenier, A, Waeghemaecker, L, Wallez, J, Wantiez, M, Wartel, F, Weber, J, Willocquet, J, Wizla, N, Wolschies, E, Zaharia, O, Zaoui, S, Zalar, A, Zaouri, B, Zellweger, A, Ziade, C, Beaugerie, L, Allez, M, Ruemmele, F, Lamer, A, Roy, M, CHU Lille, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, Registre EPIMAD, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Colloid Chemistry [Potsdam], Max Planck Institute of Colloids and Interfaces, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), and Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Crohn’s disease, inflammatory bowel disease, complication, genetics, prediction, prognosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background The identification of patients at high risk of a disabling disease course would be invaluable in guiding initial therapy in Crohn’s disease (CD). Our objective was to evaluate a combination of clinical, serological, and genetic factors to predict complicated disease course in pediatric-onset CD. Methods Data for pediatric-onset CD patients, diagnosed before 17 years of age between 1988 and 2004 and followed more than 5 years, were extracted from the population-based EPIMAD registry. The main outcome was defined by the occurrence of complicated behavior (stricturing or penetrating) and/or intestinal resection within the 5 years following diagnosis. Lasso logistic regression models were used to build a predictive model based on clinical data at diagnosis, serological data (ASCA, pANCA, anti-OmpC, anti-Cbir1, anti-Fla2, anti-Flax), and 369 candidate single nucleotide polymorphisms. Results In total, 156 children with an inflammatory (B1) disease at diagnosis were included. Among them, 35% (n = 54) progressed to a complicated behavior or an intestinal resection within the 5 years following diagnosis. The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination and good calibration, with an area under the curve of 0.80 after correction for optimism bias (sensitivity, 79%, specificity, 74%, positive predictive value, 61%, negative predictive value, 87%). Decision curve analysis confirmed the clinical utility of the model. Conclusions A combination of clinical, serotypic, and genotypic variables can predict disease progression in this population-based pediatric-onset CD cohort. Independent validation is needed before it can be used in clinical practice.

Published
2023
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7. Pratique de l'échographie clinique au sein d'un réseau territorial d'urgence.

Author

Lesage, B., Martinez, M., Lefebvre, T., Cavalli, P., Cailasson, L., Léger, M., d'Arras, A. C., Boyer, A., Redjaline, A., and Viallon, A.

Abstract

Copyright of Annales Françaises de Médecine d'Urgence is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2019
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8. Efficacy and tolerability of chitin-glucan combined with simethicone (GASTRAP ® DIRECT) in irritable bowel syndrome: A prospective, open-label, multicenter study.

Author

Talbodec N, Le Roy P, Fournier P, Lesage B, Lepoutre E, Castex F, Godchaux JM, Vandeville L, Bismuth B, Lesage X, Bayart P, Genin M, Rousseaux C, Maquet V, Modica S, Desreumaux P, and Valibouze C

Abstract

Background: Irritable bowel syndrome (IBS), defined according to the Rome IV diagnostic criteria, is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain related to altered bowel habits. First-line recommended treatments are limited to combining drugs targeting predominant symptoms, particularly pain (antispasmodics), constipation (laxatives), and diarrhea (loperamide), yielding only a limited therapeutic gain. GASTRAP ® DIRECT is a class IIa medical formulation composed of a combination of chitin-glucan and simethicone indicated for the symptomatic treatment of gas-related gastrointestinal disorders by combining different mechanisms of action., Aim: To evaluate the efficacy, tolerability, and safety of 4-week GASTRAP ® DIRECT treatment in patients with IBS., Methods: In this prospective, multicenter, open-label trial, 120 patients with IBS received three sticks of GASTRAP ® DIRECT (1.5 g/d of chitin-glucan and 0.75 mg/d of simethicone) per day for 4 weeks. The primary endpoint was the responder rate, defined as the number of patients whose abdominal pain score decreased by ≥ 30% from baseline to week (W) 4. The analysis was performed using the per-protocol set. Cardinal symptoms, impact of global symptoms on daily life, change in stool consistency, and improvement in defecatory disorders were evaluated., Results: Overall, 100 patients were evaluated. At W4, 67% (95%CI: 57-75) showed improvement in abdominal pain (score: 5.8 ± 2.4 vs 2.9 ± 2.0, P < 0.0001). Similar improvements were observed for bloating [8.0 ± 1.7 vs 4.7 ± 2.9, P < 0.0001; 60% (95%CI: 50-70) responders], abdominal distension [7.2 ± 2.1 vs 4.4 ± 3.1, P < 0.0001; 53% (95%CI: 43-63) responders], and impact of global symptoms on daily life [7.1 ± 2.0 vs 4.6 ± 2.9, P < 0.0001; 54% (95%CI: 44-64) responders]. Stool consistency improved in most patients (90% and 57% for patients with liquid and hard stools, respectively). Overall, 42% of patients with defecatory disorders reported very much/considerable improvements by W2. No severe adverse event occurred, and tolerability was rated "good" or "very good" by 93% of patients., Conclusion: GASTRAP ® DIRECT is safe and well tolerated, alleviating IBS symptoms rapidly in 2 weeks. This open-label study suggests that the combination of chitin-glucan and simethicone could be beneficial in patients with IBS., Competing Interests: Conflict-of-interest statement: Desreumaux P reports receiving personal fees from Abbvie, Abbott, Amgen, Biocodex, Biofortis, Biogen, Biokuris, Ferring, Fresenius, Janssen, Kitozyme, Lesaffre, MSD, Norgine, Pfizer, Sandoz, Shire, Takeda, Tillotts, and UCB outside the submitted work. Dr. Desreumaux has a patent (WO2009103884) issued. Veronique Maquet is a product development manager at Kitozyme. Salvatore Modica is chief operating officer at Biokuris, a spin-off company of Kitozyme. Christel Rousseaux reports other from Biotech Companies, outside the submitted work. The other authors declare no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Published
2024
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9. 3D imaging of a nuclear reactor using muography measurements.

Author

Procureur S, Attié D, Gallego L, Gomez H, Gonzales P, Lefèvre B, Lehuraux M, Lesage B, Mandjavidze I, Mas P, and Pomarède D

Abstract

The inspection of very large or thick structures represents one of the biggest challenges for nondestructive techniques. For such objects, a particularly powerful technique is muography, which makes use of free, natural cosmic-ray muons. Among other applications, this technique has been applied to provide two-dimensional (2D) images of nuclear reactors, pyramids, or volcanos. Recently, 3D algorithms developed for medical applications were adapted to the special case of muon imaging to derive density maps. The main difficulties relate to the size of the object and to the limited number of available projections. Here, we report on the first 3D imaging of a whole nuclear reactor, obtained without any prior information on its structure and using the largest set of muographic projections ever made in this field.

Published
2023
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10. Split-BioID: a proximity biotinylation assay for dimerization-dependent protein interactions.

Author

De Munter S, Görnemann J, Derua R, Lesage B, Qian J, Heroes E, Waelkens E, Van Eynde A, Beullens M, and Bollen M

Subjects
Biotinylation, Genetic Complementation Test, HEK293 Cells, Humans, Reproducibility of Results, Biological Assay methods, Dimerization, Protein Interaction Mapping
Abstract

The biotin identification (BioID) protocol uses a mutant of the biotin ligase BirA (BirA*) fused to a protein-of-interest to biotinylate proximate proteins in intact cells. Here, we show that two inactive halves of BirA* separately fused to a catalytic and regulatory subunit of protein phosphatase PP1 reconstitute a functional BirA* enzyme upon heterodimerization of the phosphatase subunits. We also demonstrate that this BirA* fragment complementation approach, termed split-BioID, can be used to screen for substrates and other protein interactors of PP1 holoenzymes. Split-BioID is a novel and versatile tool for the identification of (transient) interactors of protein dimers., (© 2016 Federation of European Biochemical Societies.)

Published
2017
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11. The transcription factor ERG recruits CCR4-NOT to control mRNA decay and mitotic progression.

Author

Rambout X, Detiffe C, Bruyr J, Mariavelle E, Cherkaoui M, Brohée S, Demoitié P, Lebrun M, Soin R, Lesage B, Guedri K, Beullens M, Bollen M, Farazi TA, Kettmann R, Struman I, Hill DE, Vidal M, Kruys V, Simonis N, Twizere JC, and Dequiedt F

Subjects
Aurora Kinases genetics, Aurora Kinases metabolism, Cell Line, Tumor, Fibroblasts cytology, Fibroblasts metabolism, HEK293 Cells, HeLa Cells, Humans, Osteoblasts cytology, Osteoblasts metabolism, Proto-Oncogene Protein c-fli-1 genetics, Proto-Oncogene Protein c-fli-1 metabolism, RNA Stability, RNA, Messenger metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, RNA-Binding Proteins metabolism, Repressor Proteins antagonists & inhibitors, Repressor Proteins metabolism, Signal Transduction, Transcriptional Regulator ERG antagonists & inhibitors, Transcriptional Regulator ERG genetics, Transcriptional Regulator ERG metabolism, Mitosis, RNA Processing, Post-Transcriptional, RNA, Messenger genetics, RNA-Binding Proteins genetics, Repressor Proteins genetics
Abstract

Control of mRNA levels, a fundamental aspect in the regulation of gene expression, is achieved through a balance between mRNA synthesis and decay. E26-related gene (Erg) proteins are canonical transcription factors whose previously described functions are confined to the control of mRNA synthesis. Here, we report that ERG also regulates gene expression by affecting mRNA stability and identify the molecular mechanisms underlying this function in human cells. ERG is recruited to mRNAs via interaction with the RNA-binding protein RBPMS, and it promotes mRNA decay by binding CNOT2, a component of the CCR4-NOT deadenylation complex. Transcriptome-wide mRNA stability analysis revealed that ERG controls the degradation of a subset of mRNAs highly connected to Aurora signaling, whose decay during S phase is necessary for mitotic progression. Our data indicate that control of gene expression by mammalian transcription factors may follow a more complex scheme than previously anticipated, integrating mRNA synthesis and degradation.

Published
2016
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12. Cdk1 orders mitotic events through coordination of a chromosome-associated phosphatase switch.

Author

Qian J, Beullens M, Huang J, De Munter S, Lesage B, and Bollen M

Subjects
Anaphase, CDC2 Protein Kinase, Cell Line, Tumor, Chromosomes metabolism, Cyclin-Dependent Kinases metabolism, Fluorescent Antibody Technique, HEK293 Cells, HeLa Cells, Humans, Microscopy, Confocal, Nuclear Envelope metabolism, Phosphoric Monoester Hydrolases, Prometaphase, Aurora Kinase B metabolism, Carrier Proteins metabolism, Cell Cycle Proteins metabolism, Cyclin-Dependent Kinases genetics, Mitosis genetics, Nuclear Proteins metabolism, Protein Phosphatase 1 metabolism, Protein Phosphatase 2 metabolism, beta Karyopherins metabolism
Abstract

RepoMan is a scaffold for signalling by mitotic phosphatases at the chromosomes. During (pro)metaphase, RepoMan-associated protein phosphatases PP1 and PP2A-B56 regulate the chromosome targeting of Aurora-B kinase and RepoMan, respectively. Here we show that this task division is critically dependent on the phosphorylation of RepoMan by protein kinase Cyclin-dependent kinase 1 (Cdk1), which reduces the binding of PP1 but facilitates the recruitment of PP2A-B56. The inactivation of Cdk1 in early anaphase reverses this phosphatase switch, resulting in the accumulation of PP1-RepoMan to a level that is sufficient to catalyse its own chromosome targeting in a PP2A-independent and irreversible manner. Bulk-targeted PP1-RepoMan also inactivates Aurora B and initiates nuclear-envelope reassembly through dephosphorylation-mediated recruitment of Importin β. Bypassing the Cdk1 regulation of PP1-RepoMan causes the premature dephosphorylation of its mitotic-exit substrates in prometaphase. Hence, the regulation of RepoMan-associated phosphatases by Cdk1 is essential for the timely dephosphorylation of their mitotic substrates.

Published
2015
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13. The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth.

Author

Winkler C, De Munter S, Van Dessel N, Lesage B, Heroes E, Boens S, Beullens M, Van Eynde A, and Bollen M

Subjects
Cell Death, Endoribonucleases genetics, HeLa Cells, Humans, Neoplasm Proteins genetics, Neoplasms genetics, Phosphoprotein Phosphatases genetics, Protein Phosphatase 1 genetics, Protein Phosphatase 1 metabolism, RNA-Binding Proteins genetics, Endoribonucleases metabolism, Mitosis, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Neoplasms enzymology, Phosphoprotein Phosphatases metabolism, Protein Phosphatase 1 antagonists & inhibitors, RNA-Binding Proteins metabolism
Abstract

The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitotic-arrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe., (© 2015. Published by The Company of Biologists Ltd.)

Published
2015
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14. Protein phosphatase PP1-NIPP1 activates mesenchymal genes in HeLa cells.

Author

Van Dessel N, Boens S, Lesage B, Winkler C, Görnemann J, Van Eynde A, and Bollen M

Subjects
Binding Sites, Biomarkers metabolism, Cell Proliferation, Cell Transdifferentiation, Endoribonucleases chemistry, Endoribonucleases genetics, HeLa Cells, Humans, Ligands, Mutation, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Phosphoprotein Phosphatases chemistry, Phosphoprotein Phosphatases genetics, Phosphorylation, Protein Interaction Domains and Motifs, Protein Stability, RNA-Binding Proteins chemistry, RNA-Binding Proteins genetics, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Endoribonucleases metabolism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Neoplasm Proteins metabolism, Phosphoprotein Phosphatases metabolism, Protein Processing, Post-Translational, RNA-Binding Proteins metabolism, Transcriptional Activation
Abstract

The deletion of the protein phosphatase-1 (PP1) regulator known as Nuclear Inhibitor of PP1 (NIPP1) is embryonic lethal during gastrulation, hinting at a key role of PP1-NIPP1 in lineage specification. Consistent with this notion we show here that a mild, stable overexpression of NIPP1 in HeLa cells caused a massive induction of genes of the mesenchymal lineage, in particular smooth/cardiac-muscle and matrix markers. This reprogramming was associated with the formation of actin-based stress fibers and retracting filopodia, and a reduced proliferation potential. The NIPP1-induced mesenchymal transition required functional substrate and PP1-binding domains, suggesting that it involves the selective dephosphorylation of substrates of PP1-NIPP1., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Published
2015
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