Molecular basis for the contribution of the antioxidant responsive elementto cancer chemoprevention

This article provides an overview of the mechanisms by which cancer chemopr eventive blocking agents increase the expression of detoxication and antiox idant genes. These agents all appear capable of transcriptionally activatin g a gene battery that includes NAD(P)H:quinone oxidoreductase, aldo-keto re ductases, glutathione S-transferases, gamma -glutamylcysteine synthetase, g lutathione synthetase and heme oxygenase. Gene induction occurs through the antioxidant responsive element (ARE), a process that is dependent on the N uclear Factor-Erythroid 2p45-related factors, Nrf1 and Nrf2. Under basal co nditions, these basic region leucine zipper (bZIP) transcription factors ar e located in the cytoplasm of the cell bound to Keap1, and upon challenge w ith inducing agents, they are released from Keap1 and translocate, to the n ucleus. Within the nucleus, Nrf1 and Nrf2 are recruited to the ARE as heter odimers with either small Maf proteins, FosB, c-Jun, JunD, activating trans cription factor 2 (ATF2) or ATF4. The role of protein kinases in transducin g chemical stress signals to the bZIP factors that affect gene induction th rough the ARE is discussed. (C) 2001 Elsevier Science Ireland Ltd. All righ ts reserved.