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Molecular and Cellular Biology, July 2002, p. 4638-4651, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4638-4651.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Conditional Derepression of Ferritin Synthesis in Cells Expressing a Constitutive IRP1 Mutant

Jian Wang1 and Kostas Pantopoulos1,2*

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital,1 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada2

Received 7 January 2002/ Returned for modification 20 February 2002/ Accepted 9 April 2002

Iron regulatory protein 1 (IRP1), a major posttranscriptional regulator of cellular iron and energy metabolism, is controlled by an iron-sulfur cluster switch. Cysteine-437 is critical for coordinating the cluster, and its replacement yields mutants that do not respond to iron perturbations and constitutively bind to cognate mRNA iron-responsive elements (IREs). The expression of IRP1C437S in cells has been associated with aberrations in iron homeostasis and toxicity. We have established clones of human lung (H1299) and breast (MCF7) cancer cells that express high levels of IRP1C437S in a tetracycline-inducible manner. As expected, IRP1C437S stabilizes transferrin receptor mRNA and inhibits translation of ferritin mRNA in both cell types by binding to their respective IREs. However, H1299 transfectants grown at high densities are able to overcome the IRP1C437S-mediated inhibition in ferritin synthesis. The mechanism involves neither alteration in ferritin mRNA levels nor utilization of alternative transcription start sites to eliminate the IRE or relocate it in less inhibitory downstream positions. The derepression of ferritin mRNA translation occurs under conditions where global protein synthesis appears to be impaired, as judged by a significant enrichment in the expression of the underphosphorylated form of the translational regulator 4E-BP1. Collectively, these data document an example where ferritin mRNA translation evades control of the IRE-IRP system. The physiological implications of this response are reflected in protection against iron-mediated toxicity, oxidative stress, and apoptosis.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal, Quebec H3T 1E2, Canada. Phone: (514) 340-8260, ext. 5293. Fax: (514) 340-7502. E-mail: kostas.pantopoulos{at}mcgill.ca.

Molecular and Cellular Biology, July 2002, p. 4638-4651, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4638-4651.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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