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Molecular and Cellular Biology, August 2000, p. 5818-5827, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Coordinate Transcriptional and Translational Regulation of Ferritin in Response to Oxidative Stress

Yoshiaki Tsuji,1,3,* Hitoshi Ayaki,1,3 Susan P. Whitman,1,3 Charles S. Morrow,2,3 Suzy V. Torti,2,3 and Frank M. Torti1,3

Departments of Cancer Biology1 and Biochemistry2 and the Comprehensive Cancer Center,3 Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Received 2 February 2000/Returned for modification 6 April 2000/Accepted 18 May 2000

The global increase in transcription of cytoprotective genes induced in response to oxidative challenge has been termed the antioxidant response. Ferritin serves as the major iron-binding protein in nonhematopoietic tissues, limiting the catalytic availability of iron for participation in oxygen radical generation. Here we demonstrate that ferritin is a participant in the antioxidant response through a genetically defined electrophile response element (EpRE). The EpRE of ferritin H identified in this report exhibits sequence similarity to EpRE motifs found in antioxidant response genes such as those encoding NAD(P)H:quinone reductase, glutathione S-transferase, and heme oxygenase. However, the EpRE of ferritin H is unusual in structure, comprising two bidirectional motifs arranged in opposing directions on complementary DNA strands. In addition to EpRE-mediated transcriptional activation, we demonstrate that ferritin is subject to time-dependent translational control through regulation of iron-regulatory proteins (IRP). Although IRP-1 is initially activated to its RNA binding (ferritin-repressing) state by oxidants, it rapidly returns to its basal state. This permits the translation of newly synthesized ferritin transcripts and ultimately leads to increased levels of ferritin protein synthesis following oxidant exposure. Taken together, these results clarify the complex transcriptional and translational regulatory mechanisms that contribute to ferritin regulation in response to prooxidant stress and establish a role for ferritin in the antioxidant response.

* Corresponding author. Mailing address: Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Phone: (336) 716-0232. Fax: (336) 716-0255. E-mail: ytsuji{at}wfubmc.edu.

Molecular and Cellular Biology, August 2000, p. 5818-5827, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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