Ferritin mRNA translation, structure, and gene transcription during development of animals and plants.

Changes in transcription/accumulation of ferritin mRNA accompany cell differentiation and development as cells establish the pattern of iron storage and metabolism that matches their specialized features. Signals which induce changes in ferritin gene expression include hormones (thyrotropin in thyroid cells), monokines (tumor necrosis factor alpha in myoblasts, and preadipocytes), phagocytosis and/or inducing agents (erythrophagocytosis in macrophages, phorbol esters in promyelocytes, and dimethyslulfoxide in proerythroblasts), heat shock (in red cells) and light (in leaf mesophyll). Iron, which has a major effect on the translation of ferritin mRNA, also leads to synthesis and/or accumulation of ferritin mRNA in hepatocytes, adult red cells, HeLa cells, and undifferentiated plant cells. Iron-induced changes in ferritin mRNA composition allow cells to synthesize large amounts of different ferritins in response to excess iron. Whether iron will act both on translation and transcription may relate to the uses of stored iron by the cell (iron reserve for other cells? detoxification?) and the magnitude of the iron signal relative to the existing pool of ferritin mRNA. Translational regulation of ferritin mRNA depends on two distinctive features of the RNA: (1) conserved regulatory sequence of 28 nucleotides occurs in the 5' noncoding region (iron 'regulatory' or 'responsive' element, IRE) which interacts with cytoplasmic regulator proteins, present in animal cells, that block initiation; sequences in the 3' untranslated region can modulate translation when the IRE is present. (2) Ferritin mRNA, either deregulated by iron induction in cells or isolated from cells (polyA+), forms initiation complexes efficiently compared to other cellular mRNAs. The structure of the IRE, which is also found in the 3' untranslated region of the iron-destabilized transferrin receptor mRNA, has begun to be analyzed by computer prediction, site-directed mutagenesis, and solution behavior. The results to date show that the IRE is a hairpin with bulges and loops that is stacked upon a base-paired flanking region (FL) with varying sequence. Interactions of the IRE+FL with other parts of ferritin mRNA are indicated by comparing the reactivity of natural ferritin mRNA with an oligomer (n = 55). The structure of the stem nearest the hairpin loop is sequence-dependent and flexible. Variations in the distance of the IRE from the cap in various ferritin mRNAs, compensated by the length of FL, and the structural properties of the IRE+FL suggest that the 5' regulatory structure of ferritin mRNA includes the IRE+FL.