FERRITIN GENE-EXPRESSION IN HEALTH AND MALIGNANCY

Intracellular iron can be stored in the protein shell of ferritin to protect the cell against the toxic action of the iron. In response to increased cell iron, more ferritin subunits are synthesized using translational and transcriptional mechanisms. Translational control involves a unique stem-loop structure in the 5' untranslated region of the subunit messengers. When iron level is low, a protein binds to this stem-loop structure and prevents translation. When intracellular iron level rises, the repressor protein is discharged and the large population of messengers begins to translate subunits. Similar stem-loop motifs occur in the 3' untranslated region of the transferrin receptor messenger where they regulate breakdown of the receptor mRNA. Finally, the presence of excess iron preferentially stimulates transcription of more ferritin message of one type (L-mRNA) which produces ferritin shells favoring iron storage. In this way, protection of the cell against iron excess is enhanced by coordinate changes in rate of synthesis of ferritin mRNA of the L-type, by release of ferritin mRNA stored in the cytoplasm, and by a reduction in the number of receptors for accepting iron into the cell. The application of these principles with reference to malignant cells is discussed.