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.
Highlights
Cell growth, proliferation and progression through the cell cycle strongly depend on the synthesis of new proteins (Pardee, 1989; Polymenis and Aramayo, 2015)
The mechanistic target of rapamycin complex 1, e.g., functions as a signaling node that adjusts protein synthesis to cell growth rates and the metabolic status of the cell (Laplante and Sabatini, 2012). mTORC1 directly phosphorylates 4E-BPs, thereby promoting the translation of a distinct group of mRNAs that strongly depend on the eukaryotic translation initiation factor 4E (Gandin et al, 2016; Nandagopal and Roux, 2015). mTORC1 further enhances the translation of mRNAs containing a 5’ terminal oligo pyrimidine tract (5’TOP) motif, which includes many mRNAs encoding ribosomal proteins and translation factors (Meyuhas and Kahan, 2015)
Since both HEK293T wild type (WT) and La related protein 1 (LARP1)-/- cells responded to CDK1i by a reduction of polysomes (Fig. S7E–G), we concluded that LARP1 is not linked to the effect on global protein synthesis, while it does mediate the specific effect of CDK1 on enhancing 5’TOP mRNA
Summary
Proliferation and progression through the cell cycle strongly depend on the synthesis of new proteins (Pardee, 1989; Polymenis and Aramayo, 2015). Cells exert temporal control over the production of specific proteins during the different phases of the cell cycle (Aviner et al, 2013; Stumpf et al, 2013; Tanenbaum et al, 2015). While Myc mostly controls translation through transcriptional upregulation of ribosomal components and translation factors (van Riggelen et al, 2010), the Ras/Erk signaling pathway shares some common downstream signals with mTORC1 including phosphorylation of ribosomal protein S6 (RPS6) (Roux and Topisirovic, 2018). Since cell cycle-associated kinases were among the primary candidates identified by the screen, we chose to pursue CDK1 and characterize its role in protein synthesis. Our results demonstrate that CDK1 acts outside of mitosis as a general activator of translation that allows direct adaptation of protein synthesis to the rate of cell proliferation
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