mTORC1 activity oscillates throughout the cell cycle promoting mitotic entry and differentially influencing autophagy induction.

Autor:	Joshi JN; Molecular Biosciences Program, Rutgers University, Piscataway, NJ, USA.; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA., Lerner AD; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA., Scallo F; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA.; Present affiliation: Yale School of Medicine, New Haven, CT, USA., Grumet AN; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA., Matteson P; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA., Millonig JH; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA.; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA., Valvezan AJ; Center for Advanced Biotechnology and Medicine, Piscataway, NJ, USA.; Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 07. Date of Electronic Publication: 2024 Feb 07.
DOI:	10.1101/2024.02.06.579216
Abstrakt:	Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that stimulates anabolic cell growth while suppressing catabolic processes such as autophagy. mTORC1 is active in most, if not all, proliferating eukaryotic cells. However, it remains unclear whether and how mTORC1 activity changes from one cell cycle phase to another. Here we tracked mTORC1 activity through the complete cell cycle and uncover oscillations in its activity. We find that mTORC1 activity peaks in S and G2, and is lowest in mitosis and G1. We further demonstrate that multiple mechanisms are involved in controlling this oscillation. The interphase oscillation is mediated through the TSC complex, an upstream negative regulator of mTORC1, but is independent of major known regulatory inputs to the TSC complex, including Akt, Mek/Erk, and CDK4/6 signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex, and instead involves CDK1-dependent control of the subcellular localization of mTORC1 itself. Functionally, we find that in addition to its well-established role in promoting progression through G1, mTORC1 also promotes progression through S and G2, and is important for satisfying the Wee1- and Chk1- dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific functional consequences in proliferating cells. Competing Interests: Declaration of Interests The authors declare no competing interests.
Databáze:	MEDLINE
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