Guanine analog-induced differentiation of human promyelocytic leukemia cells and changes in queuine modification of tRNA.
Treatment of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient human promyelocytic leukemia (HL-60) cells with 6-thioguanine results in growth inhibition and cell differentiation. 6-Thioguanine is a substrate for the tRNA modification enzyme tRNA-guanine ribosyltransferase, which normally catalyzes the exchange of queuine for guanine in position 1 of the anticodon of tRNAs for asparagine, aspartic acid, histidine, and tyrosine. During the early stages of HGPRT-deficient HL-60 cell differentiation induced by 6-thioguanine, there was a transient decrease in the queuine content of tRNA, and changes in the isoacceptor profiles of tRNA(His) indicate that 6-thioguanine was incorporated into the tRNA in place of queuine. Reversing this structural change in the tRNA anticodon by addition of excess exogenous queuine reversed the 6-thioguanine-induced growth inhibition and differentiation. Similar results were obtained when 8-azaguanine (another inhibitor of queuine modification of tRNA that can be incorporated into the anticodon) replaced 6-thioguanine as the inducing agent. The data suggest a primary role for the change in queuine modification of tRNA in mediating the differentiation of HGPRT-deficient HL-60 cells induced by guanine analogs.
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation / Q000032:analysis; D001375:Azaguanine / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency; D015470:Leukemia, Myeloid, Acute; D009580:Nitroblue Tetrazolium; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012343:RNA, Transfer / Q000378:metabolism*; D013866:Thioguanine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology*
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D009580:Nitroblue Tetrazolium; D006147:Guanine; C019549:queuine; D012343:RNA, Transfer; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D001375:Azaguanine