DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3
| Autor: | Lindsay R. Stolzenburg, Bertrand Leblond, Sébastien Malinge, Laurent Desire, Thierry Besson, John D. Crispino, Lauren Diebold, Daniel E. Cook, Casagrande Anne-Sophie, Benjamin J. Thompson, Rahul S. Bhansali |
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| Přispěvatelé: | Northwestern University [Evanston], Diaxonhit, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR) |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Cyclin E Genotype Transcription Genetic T-Lymphocytes Cyclin D Immunology Cyclin A Cyclin B Bone Marrow Cells 030204 cardiovascular system & hematology Protein Serine-Threonine Kinases Article 03 medical and health sciences Mice 0302 clinical medicine Cyclin-dependent kinase Animals Humans Immunology and Allergy [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Cyclin D3 Alleles 030304 developmental biology Cell Proliferation Gene Library Mice Knockout 0303 health sciences B-Lymphocytes biology Lymphopoiesis Cell Biology Exons Protein-Tyrosine Kinases Cell cycle Flow Cytometry E2F Transcription Factors Mice Inbred C57BL HEK293 Cells Mutation Cancer research biology.protein Female Protein Processing Post-Translational Cyclin A2 Signal Transduction |
| Zdroj: | Journal of Experimental Medicine Journal of Experimental Medicine, Rockefeller University Press, 2015, 212 (6), pp.723-740. ⟨10.1084/jem.20150002⟩ The Journal of Experimental Medicine |
| ISSN: | 0022-1007 1540-9538 |
| DOI: | 10.1084/jem.20150002⟩ |
| Popis: | Thompson et al. identify the dual specificity tyrosine-regulated kinase 1A (DYRK1A) as a new player in the control of lymphopoiesis. Loss of DYRK1A in mice results in Cyclin D3 stabilization and failure to repress E2F target genes, thus impairing cell cycle exit and proper pre–B and pre–T cell differentiation. Pre–B and pre–T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells’ proliferation, but little is known about its posttranslational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition in mice, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a nonphosphorylatable Cyclin D3 T283A mutant recapitulated these defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or loss. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development. |
| Databáze: | OpenAIRE |
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