Combinatorial mRNA Regulation: Iron Regulatory Proteins and Iso-iron-responsive

Combinations of RNA elements (mRNA specific) with binding proteins give a wide range of responses to biological signals from iron, oxygen, NO, or growth factors. Combinatorial regulation of transcription to coordinate synthesis of groups of proteins is well known and is exemplified by steroid hormone-responsive genes (1). Combinatorial regulation of mRNA utilization to coordinate syn-thesis of groups of proteins is unique currently to iron and oxygen metabolism in animals (2–15) (see Fig. 1). The RNA elements are called iso-iron-responsive elements (iso-IREs),1 and the binding proteins, called iso-iron regulatory proteins (iso-IRPs), are aconi-tase homologues. Examples of iso-IRE mRNAs are ferritin to con-centrate iron, TfR and DMT-1 for iron uptake, and ferroportin (Fpn1/IREG1/MTP1) for iron efflux. Several proteins for oxygen metabolism are also encoded in iso-IRE mRNAs, exemplified by aminolevulinate synthase (eALAS) in heme synthesis and mt-ac