Journal
CELL
Volume 174, Issue 1, Pages 72-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.05.009
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Funding
- NIH
- NCI [F30CA200347, 5T32CA009140, R01CA051497, R01CA57341, R01CA157846, R01AI077610, R01AI091481, R01CA077575, U54CA193489, P30CA010815, R01CA174746]
- Veterans Affairs Merit Award [I01BX001146]
- Patel Scholar Award
- Bloomberg-Kimmel Institute of Cancer Immunotherapy
- Tissue Core Facility at the H. Lee Moffitt Cancer Center and Research Institute [P30CA076292]
- NATIONAL CANCER INSTITUTE [T32CA009140, R01CA174746, U54CA193489, R01CA057341, R01CA077575, R01CA157846, P30CA010815, P30CA076292] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI077610] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001146] Funding Source: NIH RePORTER
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Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lyso-some-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.
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