DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

Benjamin J. Thompson, Rahul Bhansali, Lauren Diebold, Daniel E. Cook, Lindsay Stolzenburg, Anne Sophie Casagrande, Thierry Besson, Bertrand Leblond, Laurent Désiré, Sébastien Malinge, John D. Crispino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)953-970
Number of pages18
JournalJournal of Experimental Medicine
Volume212
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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