Modulation of intracellular ROS levels by TIGAR controls autophagy.
The p53-inducible TIGAR protein functions as a fructose-2,6-bisphosphatase, promoting the pentose phosphate pathway and helping to lower intracellular reactive oxygen species (ROS). ROS functions in the regulation of many cellular responses, including autophagy--a response to stress conditions such as nutrient starvation and metabolic stress. In this study, we show that TIGAR can modulate ROS in response to nutrient starvation or metabolic stress, and functions to inhibit autophagy. The ability of TIGAR to limit autophagy correlates strongly with the suppression of ROS, with no clear effects on the mTOR pathway, and is p53 independent. The induction of autophagy in response to loss of TIGAR can function to moderate apoptotic response by restraining ROS levels. These results reveal a complex interplay in the regulation of ROS, autophagy and apoptosis in response to TIGAR expression, and shows that proteins similar to TIGAR that regulate glycolysis can have a profound effect on the autophagic response through ROS regulation.
Bensaad
Karim
K
The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, UK.
Cheung
Eric C
EC
Vousden
Karen H
KH
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human