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The Journal of Biological Chemistry
Year: 2008  |  Volume: 283  |  Issue: 40  |  Page No.: 26956 - 26964

An Iron Responsive Element-like Stem-Loop Regulates α-Hemoglobin-stabilizing Protein mRNA

Camila O. dos Santos, Louis C. Dore, Eric Valentine, Suresh G. Shelat, Ross C. Hardison, Manik Ghosh, Wei Wang, Richard S. Eisenstein, Fernando F. Costa and Mitchell J. Weiss    

Abstract: Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of α-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free α-globin during hemoglobin synthesis. In primates, the 3`-untranslated region (UTR) of AHSP mRNA contains a nucleotide sequence resembling iron responsive elements (IREs), stem-loop structures that regulate gene expression post-transcriptionally by binding iron regulatory proteins (IRPs). The AHSP IRE-like stem-loop deviates from classical consensus sequences and binds IRPs poorly in electrophoretic mobility shift assays. However, in cytoplasmic extracts, AHSP mRNA co-immunoprecipitates with IRPs in a fashion that is dependent on the stem-loop structure and inhibited by iron. Moreover, this interaction enhances AHSP mRNA stability in erythroid and heterologous cells. Our findings demonstrate that IRPs can regulate mRNA expression through non-canonical IREs and extend the repertoire of known iron-regulated genes. In addition, we illustrate a new mechanism through which hemoglobin may be modulated according to iron status.

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