Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress

The global increase in transcription of cytoprotective genes induced in res ponse to oxidative challenge has been termed the antioxidant response. Ferr itin serves as the major iron-binding protein in nonhematopoietic tissues, limiting the catalytic availability of iron for participation in oxygen rad ical generation. Here we demonstrate that ferritin is a participant in the antioxidant response through a genetically defined electrophile response el ement (EpRE). The EpRE of ferritin H identified in this report exhibits seq uence similarity to EpRE motifs found in antioxidant response genes such as those encoding NAD(P)H:quinone reductase, glutathione S-transferase. and h eme oxygenase. However, the EpRE of ferritin H is unusual in structure, com prising two bidirectional motifs arranged in opposing directions on complem entary DNA strands. In addition to EpRE-mediated transcriptional activation , we demonstrate that ferritin is subject to time-dependent translational c ontrol through regulation of iron-regulatory proteins (IRP). Although IRP-1 is initially activated to its RNA binding (ferritin-repressing) state by o xidants, it rapidly returns to its basal state. This permits the translatio n of newly synthesized ferritin transcripts and ultimately leads to increas ed levels of ferritin protein synthesis following oxidant exposure. Taken t ogether, these results clarify the complex transcriptional and translationa l regulatory mechanisms that contribute to ferritin regulation in response to prooxidant stress and establish a role for ferritin in the antioxidant r esponse.