Article ; Online: Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division.
2022 Volume 13, Issue 1, Page(s) 668
Abstract: DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs). We show here that DENR is phosphorylated on ... ...
| Abstract | DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs). We show here that DENR is phosphorylated on Serine 73 by Cyclin B/CDK1 and Cyclin A/CDK2 at the onset of mitosis, and then dephosphorylated as cells exit mitosis. Phosphorylation of Ser73 promotes mitotic stability of DENR protein and prevents its cleavage at Asp26. This leads to enhanced translation of mRNAs involved in mitosis. Indeed, we find that roughly 40% of all mRNAs with elevated translation in mitosis are DENR targets. In the absence of DENR or of Ser73 phosphorylation, cells display elevated levels of aberrant mitoses and cell death. This provides a mechanism how the cell cycle regulates translation of a subset of mitotically relevant mRNAs during mitosis. |
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| MeSH term(s) | Blotting, Western ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Division/genetics ; Cell Line, Tumor ; Cyclin A/genetics ; Cyclin A/metabolism ; Cyclin B/genetics ; Cyclin B/metabolism ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; Eukaryotic Initiation Factors/genetics ; Eukaryotic Initiation Factors/metabolism ; HeLa Cells ; Humans ; MCF-7 Cells ; Mitosis/genetics ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Open Reading Frames/genetics ; Phosphorylation ; Protein Biosynthesis/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Serine/genetics ; Serine/metabolism |
| Chemical Substances | Cell Cycle Proteins ; Cyclin A ; Cyclin B ; DENR protein, human ; Eukaryotic Initiation Factors ; MCTS1 protein, human ; Oncogene Proteins ; RNA, Messenger ; Serine (452VLY9402) ; CDC2 Protein Kinase (EC 2.7.11.22) ; CDK1 protein, human (EC 2.7.11.22) ; CDK2 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22) |
| Language | English |
| Publishing date | 2022-02-03 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-022-28265-0 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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