CDK1 couples proliferation with protein synthesis

Katharina Haneke; Johanna Schott; Doris Lindner; Anne Kruse Hollensen; Christian Kroun Damgaard; Cyril Mongis; Michael Knop; Wilhelm Palm; Alessia Ruggieri; Georg Stoecklin

doi:10.1083/jcb.201906147

CDK1 couples proliferation with protein synthesis

J Cell Biol. 2020 Mar 2;219(3):e201906147. doi: 10.1083/jcb.201906147.

Authors

Katharina Haneke^{1

2}, Johanna Schott^{1

2}, Doris Lindner^{1

2}, Anne Kruse Hollensen³, Christian Kroun Damgaard³, Cyril Mongis², Michael Knop^{2

4}, Wilhelm Palm⁵, Alessia Ruggieri⁶, Georg Stoecklin^{1

2}

Affiliations

¹ Division of Biochemistry, Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Center for Molecular Biology of Heidelberg University, DKFZ-ZMBH Alliance, Heidelberg, Germany.
³ Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
⁴ Cell Morphogenesis and Signal Transduction, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
⁵ Cell Signaling and Metabolism, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
⁶ Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Diseases Research, University of Heidelberg, Heidelberg, Germany.

Abstract

Cell proliferation exerts a high demand on protein synthesis, yet the mechanisms coupling the two processes are not fully understood. A kinase and phosphatase screen for activators of translation, based on the formation of stress granules in human cells, revealed cell cycle-associated kinases as major candidates. CDK1 was identified as a positive regulator of global translation, and cell synchronization experiments showed that this is an extramitotic function of CDK1. Different pathways including eIF2α, 4EBP, and S6K1 signaling contribute to controlling global translation downstream of CDK1. Moreover, Ribo-Seq analysis uncovered that CDK1 exerts a particularly strong effect on the translation of 5'TOP mRNAs, which includes mRNAs encoding ribosomal proteins and several translation factors. This effect requires the 5'TOP mRNA-binding protein LARP1, concurrent to our finding that LARP1 phosphorylation is strongly dependent on CDK1. Thus, CDK1 provides a direct means to couple cell proliferation with biosynthesis of the translation machinery and the rate of protein synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Autoantigens / genetics
Autoantigens / metabolism
CDC2 Protein Kinase / genetics
CDC2 Protein Kinase / metabolism*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Proliferation*
Eukaryotic Initiation Factor-2 / genetics
Eukaryotic Initiation Factor-2 / metabolism
Eukaryotic Initiation Factors / genetics
Eukaryotic Initiation Factors / metabolism
Female
Fibroblasts / enzymology
Gene Expression Regulation, Enzymologic
HEK293 Cells
HeLa Cells
Humans
Kinetics
Mice, Inbred C57BL
Phosphorylation
Protein Biosynthesis
RNA 5' Terminal Oligopyrimidine Sequence
RNA, Messenger / genetics
RNA, Messenger / metabolism
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
SS-B Antigen
Signal Transduction
Uterine Cervical Neoplasms / enzymology*
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / pathology

Substances

Adaptor Proteins, Signal Transducing
Autoantigens
Cell Cycle Proteins
EIF4EBP1 protein, human
EIF4EBP2 protein, human
Eukaryotic Initiation Factor-2
Eukaryotic Initiation Factors
RNA, Messenger
Ribonucleoproteins
Ribosomal Protein S6 Kinases, 70-kDa
ribosomal protein S6 kinase, 70kD, polypeptide 1
CDC2 Protein Kinase
CDK1 protein, human
Cdk1 protein, mouse