EFFECTS OF IRON-DEPLETION ON CELL-CYCLE PROGRESSION IN NORMAL HUMAN T-LYMPHOCYTES - SELECTIVE-INHIBITION OF THE APPEARANCE OF THE CYCLIN A-ASSOCIATED COMPONENT OF THE P33(CDK2) KINASE

Iron removal by the chelating-agent deferoxamine (DFO) arrests cell cy cle progression of activated human T cells in late G1 phase, before th e G1/S border. The effects of the drug on molecules that regulate prog ression through the cell cycle were defined. DFO (10 mu mol/L) inhibit ed induction of transcription of the cdc2 gene, but had no effect on a ccumulation of cdk2, cdk4, or interleukin (IL)-2 transcripts. Mo detec table p34(cdc2) protein accumulated, but synthesis of the p33(cdk2) pr otein was begun, It accumulated to normal levels during the first 20 t o 30 hours of incubation in the presence of DFO. Furthermore, p33(cdk2 ) was activated as an H1 histone kinase. As active p33(cdk2) primarily represents complexes of the p33 protein with cyclin E or cyclin A, th e effects of DFO on these cyclins were examined. Although the inductio n of synthesis and early accumulation of cyclin E and cyclin E-associa ted kinase activity appeared normal, the appearance of cyclin A and cy clin A-associated kinase activity were inhibited by DFO, However, the production of cyclin A mRNA appeared to be normal in the presence of D FO. A major effect of DFO in blocking cell cycle progression may be me diated through inhibition of the appearance of cyclin A protein and, t herefore, a major component of p33(cdk2) activity, The results also in dicate that the p33(cdk2)/cyclin E activity produced in the presence o f DFO was not sufficient for completion of the G1 phase of the cell cy cle. (C) 1995 by The American Society of Hematology.