Cell cycle control of cellular metabolism through phase-specific regulation of mTOR Complex 1

Project Summary/Abstract Cellular metabolic and biosynthetic demands change throughout the cell cycle, which critically impacts cell growth, proliferation, and human disease. Understanding how cellular metabolism is modulated in different cell cycle phases is fundamental to understanding the molecular mechanisms governing cell growth and proliferation. Yet, very little is known about how metabolism changes throughout the cell cycle and how these changes mechanistically link to the cell cycle machinery. The master metabolic regulator Mechanistic Target of Rapamycin Complex 1 (mTORC1) is an evolutionarily conserved protein kinase complex that integrates upstream growth factor and nutrient signals to stimulate anabolic cell growth. mTORC1 is activated in most, if not all, proliferating eukaryotic cells, but the role of mTORC1 in controlling cellular metabolism has not been studied in distinct cell cycle phases. Thus it is unknown whether the metabolic program induced downstream of mTORC1 is differentially regulated throughout the cell cycle, or whether mTORC1 can play unique roles in specific cell cycle phases. We tracked mTORC1 activity across the full cell cycle and found that mTORC1 is acutely and differentially regulated, with its activity peaking in S/G2 and lowest in mitosis and G1. We hypothesize that mTORC1 is a crucial effector through which the cell cycle orchestrates metabolic changes, dynamically modulating metabolic pathways in a phase-specific manner to meet changing biosynthetic requirements. In this planned research program, we will elucidate the cell cycle phase-specific functions of mTORC1 by combining metabolomics and metabolic flux analysis with detailed mechanistic studies. Based on our preliminary data, we anticipate that these studies will uncover new functions of mTORC1, along with new regulatory mechanisms, that are not evident in studies on asynchronous cell populations, thus providing critical new insights into the fundamental mechanisms that integrate cell cycle control with cellular metabolism.