Nrf2 mediates inducer-dependent activation of the heme oxygenase-1 (HO-1) gene (Alam, J., Stewart, D., Touchard, C., Boinapally, S., Choi, A. M., and Cook, J. L. (1999) J. Biol. Chem. 274, 26071-26078), but the mechanism by which HO-1 inducers regulate Nrf2 function is not known. Treatment of mouse hepatoma (Hepa) cells with 50 microm CdCl(2) increased the amount of Nrf2 protein in a time-dependent manner; induction was observed within 30 min, prior to the accumulation of HO-1 mRNA. Cadmium did not significantly affect the steady-state level of Nrf2 mRNA or the initial rate of Nrf2 protein synthesis but increased the half-life of Nrf2 from approximately 13 to 100 min. Proteasome inhibitors, but not other protease inhibitors, enhanced the expression of Nrf2, and ubiquitinylated Nrf2 was detected after proteasome inhibition. Cycloheximide inhibited cadmium-stimulated Nrf2 expression and DNA binding activity and attenuated HO-1 mRNA accumulation. Conversely, proteasome inhibitors enhanced HO-1 mRNA and protein accumulation by a Nrf2-dependent mechanism. Together, these results indicate that Nrf2 is targeted for rapid degradation by the ubiquitin-proteasome pathway and that cadmium delays the rate of Nrf2 degradation leading to ho-1 gene activation.