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

Authors :
Thompson BJ
Bhansali R
Diebold L
Cook DE
Stolzenburg L
Casagrande AS
Besson T
Leblond B
Désiré L
Malinge S
Crispino JD
Source :
The Journal of experimental medicine [J Exp Med] 2015 Jun 01; Vol. 212 (6), pp. 953-70. Date of Electronic Publication: 2015 May 25.
Publication Year :
2015

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.<br /> (© 2015 Thompson et al.)

Details

Language :
English
ISSN :
1540-9538
Volume :
212
Issue :
6
Database :
MEDLINE
Journal :
The Journal of experimental medicine
Publication Type :
Academic Journal
Accession number :
26008897
Full Text :
https://doi.org/10.1084/jem.20150002