LACK OF COORDINATE CONTROL OF FERRITIN AND TRANSFERRIN RECEPTOR EXPRESSION DURING RAT-LIVER REGENERATION

Transferrin receptor (TfR) and ferritin, key proteins of cellular iron metabolism, are coordinately and divergently controlled by cytoplasmi c proteins (iron regulatory proteins, IRP-1 and IRP-2) that bind to co nserved mRNA motifs called iron-responsive elements (IRE). IRP, in res ponse to specific stimuli (low iron levels, growth and stress signals) are activated and prevent TfR mRNA degradation and ferritin mRNA tran slation by hindering ferritin mRNA binding to polysomes. We previously found that, in regenerating liver, IRP activation was accompanied by increased TfR mRNA levels, but not by reduced ferritin expression. The basis for this unexpected behavior was investigated in the present st udy. Liver regeneration triggered by carbon tetrachloride (CCl4) stimu lated by four- to fivefold the synthesis of both L and H ferritin chai ns. This increase was accompanied with a transcriptionally regulated t wofold rise in the amount of ferritin mRNAs. Moreover, polysome-associ ated ferritin transcripts were fourfold higher in CCl4-treated animals than in control animals. Because RNA bandshift assays showed a fourfo ld increase in IRP-2 binding activity after CCl4 administration, activ ated IRP in regenerating liver seemed unable to prevent ferritin mRNAs binding to polysomes. This was confirmed by direct demonstration in t he wheat germ translation system that the efficiency of IRP as a trans lational repressor of a mRNA bearing an IRE motif in front of a report er transcript is impaired in CCl4-treated rats in spite of an enhanced IRE-binding capacity. In conclusion, we show for the first time that the paradigm of coordinate and opposite control of ferritin and TfR by IRP is contradicted in liver regeneration. Under these circumstances, growth-dependent signals may activate ferritin gene transcription and at the same time hamper the;ability of activated IRP-2 to repress tra nslation of ferritin mRNAs, thus preserving for growing liver cells an essential iron-storage compartment.