Fig. 3

The Nrf2/Keap1 signaling pathway. Under basal conditions Nrf2 is bound by two molecules of Keap1, poly-ubiquitinylated by the Cul3 system and thereby marked for proteasomal degradation. Only a small portion of Nrf2 escapes from this degradation process and translocates to the nucleus to maintain the basal expression of anti-oxidant response genes. Under stress conditions like elevated levels of H₂O₂ Keap1 is modified at redox sensitive cysteine residues leading to an impaired conformation and inactivation of Keap1. Newly translated Nrf2 escapes ubiquitinylation, translocates to the nucleus and induces the anti-oxidative stress response. Mechanisms for the continuously accumulation of Nrf2 in the nucleus of several cancer cells can be triggered by (i) mutations of Keap1 associated with its inactivation, (ii) epigenetic silencing of Keap1 and (iii) mutations of oncogenes such as K-ras, B-raf and c-myc leading to the transcriptional induction of Nrf2.