An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA

Autor(es)

dos Santos, Camila O. ^[1] ; Dore, Louis C. ^[1] ; Valentine, Eric ^[1] ; Shelat, Suresh G. ^[2] ; Hardison, Ross C. ^[3] ; Ghosh, Manik ^[4] ; Wang, Wei ^[5] ; Eisenstein, Richard S. ^[6] ; Costa, Fernando F. ^[7] ; Weiss, Mitchell J. ^[1]

Afiliação do(s) autor(es)

^[1] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 - USA

^[2] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 - USA

^[3] Penn State Univ, Dept Biochem & Mol Biol, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 - USA

^[4] NICHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 - USA

^[5] Wake Forest Univ Hlth Sci, Dept Biochem, Winston Salem, NC 27157 - USA

^[6] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 - USA

^[7] Univ Estadual Campinas, Ctr Hemotherapy & Hematol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 283, n. 40, p. 26956-26964, OCT 3 2008.
• Citações Web of Science: 33

Resumo

Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of alpha-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free alpha-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. (AU)

• Processo FAPESP: 02/13801-7 - Alterações hereditárias das hemoglobinas: genética molecular, aspectos da evolução clínica e produção de animais transgênicos
• Beneficiário: Fernando Ferreira Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático