Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.
Iron-responsive elements (IREs) are regulatory RNA elements which are characterized by a phylogenetically defined sequence-structure motif. Their biological function is to provide a specific binding site for the IRE-binding protein (IRE-BP). Iron starvation of cells induces high affinity binding of the cytoplasmic IRE-BP to an IRE which has at least two different known biological consequences, repression of ferritin mRNA translation and stabilization of the transferrin receptor transcript. We report the identification of a novel, evolutionarily conserved IRE motif in the 5' UTR of murine and human erythroid-specific delta-aminolevulinic acid synthase (eALAS) mRNA which encodes the first, and possibly rate limiting, enzyme of the heme biosynthetic pathway. We demonstrate the function of the eALAS IRE as a specific binding site for the IRE-BP by gel retardation analyses and by in vitro translation experiments. In addition, we show that the 5' UTR of eALAS mRNA is sufficient to mediate iron-dependent translational regulation in vivo. These findings strongly suggest involvement of the IRE-IRE-BP system in the control of heme biosynthesis during erythroid differentiation.
Dandekar
T
T
European Molecular Biology Laboratory, Heidelberg FRG.
Stripecke
R
R
Gray
N K
NK
Goossen
B
B
Constable
A
A
Johansson
H E
HE
Hentze
M W
MW
D000624:5-Aminolevulinate Synthetase / Q000097:blood / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D002474:Cell-Free System / Q000378:metabolism; D016208:Databases, Factual; D015672:Erythroid Precursor Cells / Q000201:enzymology* / Q000502:physiology; D005293:Ferritins / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D035925:Iron-Regulatory Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D010920:Placenta; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000097:blood / Q000737:chemistry* / Q000378:metabolism
D002352:Carrier Proteins; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D005293:Ferritins; D000624:5-Aminolevulinate Synthetase