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Nrf-2/ARE activation pathway. Under basal conditions Nrf-2 is dimerized with KEAP1 and continuously targeted for degradation due to ubiquitination by Cul3. Electrophilies and oxidants can disrupt the dimerization of Nrf2 and KEAP directly by modifiying cysteine residues in KEAP1 or through phosphorylation of Nrf2 at Ser40 by protein kinases. Nrf2 is then free to translocate into the nucleus, bind with an adaptor protein (e.g. Mafs and ATF4) and increase ARE-driven transcription.
