DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3
- PMID: 26008897
- PMCID: PMC4451127
- DOI: 10.1084/jem.20150002
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.
© 2015 Thompson et al.
Figures
Similar articles
-
Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks.Cell Cycle. 2016 Nov;15(21):2882-2894. doi: 10.1080/15384101.2016.1198861. Epub 2016 Jun 21. Cell Cycle. 2016. PMID: 27327568 Free PMC article.
-
Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling.Cardiovasc Res. 2016 Jun 1;110(3):381-94. doi: 10.1093/cvr/cvw074. Epub 2016 Apr 7. Cardiovasc Res. 2016. PMID: 27056896
-
Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling.Nat Rev Immunol. 2014 Feb;14(2):69-80. doi: 10.1038/nri3570. Epub 2013 Dec 31. Nat Rev Immunol. 2014. PMID: 24378843 Free PMC article. Review.
-
No T without D3: a critical role for cyclin D3 in normal and malignant precursor T cells.Cancer Cell. 2003 Dec;4(6):417-8. doi: 10.1016/s1535-6108(03)00305-2. Cancer Cell. 2003. PMID: 14706330 Review.
-
Expression and activity of the retinoblastoma protein (pRB)-family proteins, p107 and p130, during L6 myoblast differentiation.Cell Growth Differ. 1995 Oct;6(10):1287-98. Cell Growth Differ. 1995. PMID: 8845306
Cited by
-
Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.Nat Methods. 2024 Jun;21(6):1033-1043. doi: 10.1038/s41592-024-02256-z. Epub 2024 Apr 29. Nat Methods. 2024. PMID: 38684783
-
Aberrant stem cell and developmental programs in pediatric leukemia.Front Cell Dev Biol. 2024 Mar 27;12:1372899. doi: 10.3389/fcell.2024.1372899. eCollection 2024. Front Cell Dev Biol. 2024. PMID: 38601080 Free PMC article. Review.
-
Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome.Sci Transl Med. 2024 Jan 24;16(731):eadd6883. doi: 10.1126/scitranslmed.add6883. Epub 2024 Jan 24. Sci Transl Med. 2024. PMID: 38266108 Free PMC article.
-
Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model.Neurobiol Dis. 2024 Jan;190:106359. doi: 10.1016/j.nbd.2023.106359. Epub 2023 Nov 20. Neurobiol Dis. 2024. PMID: 37992782 Free PMC article.
-
Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.JCI Insight. 2023 Oct 31;8(23):e172851. doi: 10.1172/jci.insight.172851. JCI Insight. 2023. PMID: 37906251 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials