Characterization of the Cellular response to Hypoxia

Abstract

Hypoxia exerts a strong inhibitory effect on mTORC1 activity. However, the mechanistic basis is currently not well understood. In my study I found that oxygen concentrations regulate mTORC1 activity in a highly dynamic manner. This rapid response of mTORC1 to changes in oxygen concentrations is independent of HIF or its transcriptional targets, REDD1 and BNIP3. The effect of hypoxia on mTORC1 is mediated through a posttranslational mechanism that likely involves a hemecontaining protein. In further studies I characterized the posttranslational regulation of REDD1 and CDC6. REDD1 is a negative regulator of mTORC1 that is transcriptionally upregulated in hypoxia. My study shows that mTORC1 increases REDD1 protein stability and reveals a novel mTORC1-REDD1 feedback loop. Finally, I found that the cell cycle-regulatory protein CDC6 is not regulated by hypoxia but is rapidly degraded upon cellular exposure to DNA-damaging agents in a manner dependent on the ubiquitin-like protein Nedd8.