抄録
Our body has ability to sense environmental insults and to activate cellular defense enzyme genes. Transcription factor Nrf2 is essential for the coordinated induction of cellular defense enzymes and protection of lung tissues through association with CNC-sMaf binding element (CsMBE or ARE/EpRE). This notion has been supported by experiments using animal models, showing that Nrf2-null mice are sensitive to a wide variety of toxic electrophiles and ROS. Keap1 acts as a subunit of ubiquitin-E3 ligase that degrades Nrf2 constitutively and as sensors for electrophilic and oxidative stresses, and covalent modifications of the cysteine residues abrogate the ubiquitin ligase activity. This system has been referred to as the Cysteine Code. The two-site recognition / hinge and latch model proposed for the Keap1-Nrf2 system describes the mechanism of nuclear accumulation of Nrf2 in a Cul3-Keap1 E3 ubiquitin ligase-dependent manner. We have verified this model through structure biology, mouse genetics, and human disease analyses. Many missense mutations have been identified in KEAP1 and NRF2 genes of human lung cancers. These mutations disrupt the KEAP1-NRF2 complex and result in constitutive activation of NRF2. Subsequently, elevated expression of NRF2 target genes confers advantages on the growth of cancer cells through the metabolic reprogramming. Thus, the Keap1-Nrf2 system opens a new avenue to the understanding of the signal transduction and regulatory processes underlying the stress response and cancer progression.
