Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP

The cartoon depicts the approximate increases in Nrf2 activity, and the resulting induction of antioxidant and detoxication cytoprotective genes (such as Gclc, Gclm, Gpx2, Hmox1, Nqo1, Srxn1 and Txnrd1) compared with metabolic genes (such as G6pdx, Me1, Mthfd2, Pgd and Tk1), that are observed in the mouse upon pharmacological inhibition of Keap1 and Pten by tert-butyl hydroquinone (tBHQ), or disruption of the Pten gene alone, or disruption of both Keap1 and Pten genes. The relative size of the arrows has been chosen to provide a rough estimate of the amount of Nrf2 protein targeted for proteasomal degradation, as opposed to the amount of Nrf2 translocated to the nucleus to support ARE-driven gene expression (or stimulate other indirect gene transactivation), and also the strength of repression through Keap1 and the PTEN−PI3K−PKB/Akt−GSK-3 pathway.271