Abstract A57: Plasticity of the translational landscape during the mammalian cell cycle: Implications and new insights for cancer cell proliferation

Abstract

Abstract Deregulated cell proliferation is a defining feature of cancer cells. Normally, an intricate regulatory network ensures proper cell cycle progression during development and for tissue homeostasis. Although many steps in gene regulation imbue specificity to this program, the translational landscape of gene expression underlying cell cycle progression remains poorly understood. To address this outstanding question, we have conducted the first genome-wide analysis of translational regulation using ribosome profiling during each phase of the cell cycle. We have uncovered widespread translational regulation of hundreds of mRNAs that provides a rapid, robust, and precise mechanism for gene regulation that underlies the cell cycle program. These include a number of genes involved in key biological process and hallmarks of cancer cell growth and tumor development including cellular proliferation, cellular metabolism, and safeguarding genomic integrity. We have further characterized a novel network of translational regulation coordinating the expression of the cohesin complex, which is important for proper chromosomal segregation, regulating transcription, and has recently been identified as a common target of mutation in a number of tumor types. Mechanistically, we show that the 5'UTRs of several cohesin mRNAs are sufficient to direct their cell cycle dependent pattern of expression. Thereby, our studies highlight an intricate relationship in translational control between the machineries responsible for maintaining the organization of the genome and protein synthesis. Moreover, we discovered that translational specificity during cell cycle phases coordinates the mTOR signaling pathway. Specifically, we uncovered that translation of RICTOR, a key component of mTORC2, is induced during S-phase, resulting in an increase in mTORC2 signaling during this phase of the cell cycle. Furthermore, we showed that rictor-/- MEFs exhibited a marked decrease in S-phase cells compared to wild-type MEFs, suggesting that RICTOR may be required to prevent premature exit from S-phase, ensuring that cells complete DNA replication. Together, our findings pinpoint that translational regulation of RICTOR underlies cell cycle-dependent mTORC2 activity, which may be a critical determinant of the mammalian cell cycle program. Our findings highlight both the prevalence and dynamic nature of translational regulation during cell cycle progression. This work further suggests a multifaceted mechanism for differential regulation of transcript-specific translational control in the accurate execution of distinct steps of the cell cycle. Current studies are unraveling novel cis-regulatory sequences underlying the molecular mechanisms governing the translational regulation of mRNA networks during the cell cycle and determining how distinct oncogenic insults, which directly impact the translational machinery, alter the expression patterns of these networks leading to uncontrolled cell cycle progression. Citation Format: Craig R. Stumpf, Melissa V. Moreno, Adam B. Olshen, Barry S. Taylor, Davide Ruggero. Plasticity of the translational landscape during the mammalian cell cycle: Implications and new insights for cancer cell proliferation. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A57.