MODULATION OF TRANSFERRIN RECEPTOR MESSENGER-RNA BY TRANSFERRIN GALLIUM IN HUMAN MYELOID HL-60 AND LYMPHOID CCRF-CEM LEUKEMIC-CELLS

Gallium binds to the iron transport protein transferrin (Tf), is incor porated into cells through transferrin receptors (TfR) and inhibits ir on-dependent DNA synthesis. Since cellular TfR expression is tightly r egulated by the availability of iron, we investigated the effects of t ransferrin-gallium (Tf-Ga) on TfR mRNA levels in myeloid HL60 and lymp hoid CCRF-CEM cells. In HL60 cells, Tf-Ga increased TfR mRNA levels in a dose-dependent fashion. This increase in TfR mRNA was blocked by Tf -Fe and by cycloheximide. Analysis of the rate of mRNA decay in the pr esence of actinomycin D revealed that the half-life of TfR mRNA was in creased in HL60 cells incubated with Tf-Ga. The rate of transcription of TfR mRNA was not increased by Tf-Ga. In contrast with HL60 cells, C CRF-CEM cells displayed a decrease in the level of TfR mRNA after incu bation with Tf-Ga. Tf-Ga inhibited iron uptake in both HL60 and CCRF-C EM cells but increased the level of TfR mRNA only in HL60 cells, sugge sting that the Tf-Ga induction of TfR mRNA was not solely due to inhib ition of cellular iron uptake. At growth-inhibitory concentrations, Tf -Ga increased the TfR mRNA level in HL60 cells but decreased it in CCR F-CEM cells. Our studies suggest that in HL60 cells, gallium regulates TfR expression at the post-transcriptional level by mechanisms which require de novo protein synthesis and involve interaction with iron. T he divergent effects of Tf-Ga on TfR mRNA in myeloid HL60 and lymphoid CCRF-CEM cells suggest that differences exist in the regulation of Tf R expression between these two cell types.