NFE2L2 (NRF2)
NRF2, encoded by NFE2L2, is a bZIP transcription factor that commands the cell’s antioxidant and detoxification program: the response to oxidative and electrophilic stress.
Function
Under basal conditions NRF2 is trapped in the cytoplasm by KEAP1, which recruits the CUL3 ubiquitin ligase and keeps the protein degraded with a half-life under half an hour. Reactive oxygen species and electrophiles modify cysteines on KEAP1, the trap releases, and NRF2 accumulates and enters the nucleus. There it binds antioxidant-response elements and induces the protective program: glutathione synthesis, NADPH generation, heme oxygenase-1, glutathione S-transferases, and proteasome subunits. The system is a graded thermostat for oxidative damage, tuned to keep the mutation supply low without suppressing the redox signals cells use for communication.
In cancer
NRF2’s role in cancer is double. As a maintenance factor it protects normal tissue from carcinogenic damage, and loss of NRF2 increases chemical carcinogenesis in mice. Once a tumor exists, the relationship inverts: many tumors carry NRF2 or KEAP1 mutations that lock NRF2 on, and the constitutive detoxification program then defends the tumor against chemotherapy and radiotherapy while supporting its reductive biosynthesis. NRF2 activation is common in lung squamous carcinoma, and high NRF2 signature correlates with chemoresistance.
Notes
- Human gene symbol: NFE2L2; UniProt Q16236; 605 amino acids; Neh2 (KEAP1-binding) and bZIP domains.