Ferritin is a ubiquitous intracellular
iron storage
protein that consists of 24 subunits of the H and L type. The ability to sequester
iron from participation in
oxygen free radical formation is consistent with a cytoprotective role for
ferritin. Here we demonstrate that
ferritins H and L are induced in cells treated with beta-napthoflavone (beta-NF) and chemopreventive dithiolethiones. Induction of
ferritin H by beta-NF and the dithiolethiones
oltipraz and
1,2-dithiole-3-thione (D3T) occurs via a transcriptional mechanism that is mediated by the
ferritin H electrophile/
antioxidant-responsive
element (EpRE/ARE). The murine
ferritin H gene contains five potential
xenobiotic-responsive
element (XRE) sequences in its 5'-promoter region. However, deletion analysis demonstrates that these XRE sequences are not functional in inducing
ferritin H in response to beta-NF. Electrophoretic mobility shift assays demonstrate that the
ferritin H EpRE/ARE binds Nrf2. Transfection of chimeric
ferritin H reporter genes with Nrf2 expression vectors and Nrf2 dominant-negative mutants indicate that Nrf2 functions at the EpRE/ARE to mediate transcriptional activation of
ferritin H. Induction of
ferritin H and L was not seen in Nrf2 knockout cells, demonstrating that this
transcription factor is required for the induction of
ferritin in response to polycyclic aromatic
xenobiotics and chemopreventive agents. Nrf2 may also play a role in basal transcription of both
ferritin H and L. These results provide a mechanistic link between regulation of the
iron storage
protein ferritin and the
cancer chemopreventive response.