Nrf2 Transcription Factor Can Directly Regulate mTOR: LINKING CYTOPROTECTIVE GENE EXPRESSION TO A MAJOR METABOLIC REGULATOR THAT GENERATES REDOX ACTIVITY.

Nrf2 is a master transcription factor that regulates a wide variety of cellular proteins by recognizing and binding to antioxidant response elements (AREs) in their gene promoter regions. In this study we show that increasing cellular Nrf2 results in transcriptional activation of the gene for mTOR, which is central to the PI3K signaling pathway. This is the case in cells with normal physiological PI3K. However, in cells with abnormally active PI3K increased cellular Nrf2 levels have no effect on mTOR. ChIP assays results show that increased Nrf2 binding is associated with decreased p65 binding and H3-K27me3 signal (marker of gene repression) as well as increased H3-K4me3 signal (marker of gene activation). However, in cells with PI3K activation, no effect of cellular Nrf2 increase on mTOR transcription was observed. In these cells, increasing Nrf2 levels increases Nrf2 promoter binding marginally, whereas p65 binding and H3-K27me3 mark were significantly increased, and H3-K4me3 signal is reduced. Together, these data show for the first time that Nrf2 directly regulates mTOR transcription when the PI3K pathway is intact, whereas this function is lost when PI3K is activated. We have identified a link between the Nrf2 system of sensing environmental stress and mTOR, which is a key cellular protein in metabolism. Studies in cells with activating mutations in the PI3K pathway suggest that Nrf2 transcriptional regulation of mTOR is related to promoter binding of p65 and of methylation of histone residues permissive of transcription.