Revised Manuscript Received February 17, 1993 abstract: Transferrin, the transferrin receptor, and ferritin are integral tothe body’s management of iron, an element requiredfor life but highly toxic when present in excess. The transferrin receptor and ferritin are regulated posttranscriptionally by iron: the transferrin receptor by mRNA stability and ferritin by mRNA translation. Results describedhere indicatethat transferrin, like ferritin, is regulated by iron at the level of translation. Chimeric genes introduced into the mouse genome were composed of the human transferrin 5'regulatory regionfused to the chloramphenicol acetyl transferase (CAT) reporter gene. Iron administration to transgenic mice resulted in a significant decrease of transferrin-directed CAT enzyme activity and CAT protein in liver, but no significant decrease in human transferrin-CATmRNA levels. Binding of specific RNA iron regulatory elements by proteins in cytoplasmic extracts have been shown to regulate ferritin and transferrin receptorsynthesis. Similar results have been obtained with transferrin mRNA. A decreased binding of human transferrin 5'-untranslated region RNA by factorsin cytoplasmic extracts of livers from mice receiving iron was found when compared to extracts from control mice. A human transferrin RNA-protein complex migrated electrophoreticallywith the same mobility as a ferritin iron responsive element RNA-iron responsive element binding protein complex. The ferritin iron responsive element RNA also competed with the humantransferrin 5'-untranslated region RNA-protein complexes formed and vice versa. Therefore, iron modulation of human transferrin may share a factor common or similar to that observed in ferritin and transferrin receptor iron modulation.

Transferrin (TF),* 1 the major plasma protein which binds and transports iron, is regulated in humans and rats by iron levels. In rats, iron deficiency induced by diet stimulates liver TF synthesis at the level of transcription, yet chronic iron overload does not affect levels of serum TF (Idzerda et al., 1986). However, in cultured rat hepatocytes, levels of secreted TF decrease with irontreatment which appears to modulate TF posttranscriptionally (Lescoat et al., 1989). In humans, iron overloadleads to a decrease in TF expression while iron