title: DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Thompson
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhansali
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208.
authors.forename: Lauren
authors.initials: L
authors.lastname: Diebold
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Cook
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stolzenburg
authors.affiliation: Diaxonhit, 75013 Paris, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Casagrande
authors.affiliation: Normandie Université, COBRA, UMR 6014 and FR 3038; Université Rouen; INSA Rouen; Centre National de la Recherche Scientifique, Bâtiment IRCOF, 76821 Mont St. Aignan, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Besson
authors.affiliation: Diaxonhit, 75013 Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Leblond
authors.affiliation: Diaxonhit, 75013 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désiré
authors.affiliation: INSERM U985, Gustave Roussy, 94800 Villejuif, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Malinge
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60208 j-crispino@northwestern.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D056743:Cyclin D3 / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000378:metabolism; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D015723:Gene Library; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D038041:Lymphopoiesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D014158:Transcription, Genetic; D000097603:Dyrk Kinases
chemical_list: D056743:Cyclin D3; D050684:E2F Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C534697:Ccnd3 protein, mouse