IRON AT THE CELL-SURFACE CONTROLS BOTH DNA-SYNTHESIS AND PLASMA-MEMBRANE REDOX SYSTEM

Addition of the impermeable iron II chelator bathophenanthroline disul fonate (BPS) to cultured Chinese hamster lung fibroblast (CCL 39 cells ) inhibits DNA synthesis but not protein synthesis or cytoplasmic alka linization, when cell growth is initiated with growth factors such as EGF plus insulin, thrombin, or ceruloplasmin. The BPS inhibition is re versed by addition of stoichiometric ferrous iron at stoichiometric co ncentration. BPS does not inhibit cell growth stimulated by fetal calf serum. The effect of the BPS differs from the inhibition of growth by hydroxyurea which acts on the ribonucleotide reductase. The BPS treat ment leads to release of iron from the cells as determined by BPS iron II complex formation over 90 min. Cells treated with BPS just during starvation period cannot re-initiate DNA synthesis after mitogen stimu lation even if BPS is removed from the medium and cells are previously washed. BPS treatment also inhibits transplasma membrane electron whi ch is restored by incubation of cells with 10 mu M ferric ammonium cit rate. Growth factor stimulation of DNA synthesis is restored by additi on of 1 mu M ferrous ammonium sulfate or ferric ammonium citrate, or 0 .1 mu M diferric transferrin. Copper, cobalt, nickel, zinc, gallium, a luminum, or apotransferrin cannot restore the activity. The BPS effect is consistent with removal of iron from a site on the cell surface wh ich controls electron transport and DNA synthesis.