Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Chi V. Dang

Abstract

Recent reports indicate 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, recapitulating 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 acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, inhibiting activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation, revealing a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.

Embargoed

Available to all on Saturday, September 11, 2021

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS