mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human & mouse cell lines (live single-cell imaging) |
| Journal | Cell Reports |
| Year | 2024 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.celrep.2024.114543 · PMID 39067023 · Free full text (PMC12730006) |
Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. mTORC1 has long been known to promote progression through G1. We find that mTORC1 also promotes progression through S and G2 and is important for satisfying the Chk1/Wee1-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 consequences for proliferating cells.
| Intervention | Partial mTORC1 inhibition; nutrient reduction; cell-cycle synchronization |
| Target | mTORC1 / TSC complex |
| Model | Human & mouse cell lines |
| Effect | mTORC1 activity oscillates across the cell cycle (low mitosis/G1, high S/G2); low-mTORC1 G1 cells are more sensitive to autophagy induction |