Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 leukemia cells.
Tiazofurin (2-beta-D-ribofuranosyl-4-thiazole-carboxamide; NSC 286193), an antitumor carbon-linked nucleoside that inhibits IMP dehydrogenase (IMP:NAD+ oxidoreductase; EC 1.1.1.205) and depletes guanylate levels, can activate the erythroid differentiation program of K-562 human leukemia cells. Tiazofurin-mediated cell differentiation is a multistep process. The inducer initiates early (less than 6 hr) metabolic changes that precede commitment to differentiation; among these early changes are decreases in IMP dehydrogenase activity and in GTP concentration, as well as alterations in the expression of certain protooncogenes (c-Ki-ras). K-562 cells do express commitment-i.e., cells exhibit differentiation without tiazofurin. Guanosine was effective in preventing the action of tiazofurin, thus providing evidence that the guanine nucleotides are critically involved in tiazofurin-initiated differentiation. Activation of transcription of the erythroid-specific gene that encodes A gamma-globin is a late (48 hr) but striking effect of tiazofurin. Down-regulation of the c-ras gene appears to be part of the complex process associated with tiazofurin-induced erythroid differentiation and relates to the perturbations of GTP metabolism.
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D011905:Genes, ras / Q000187:drug effects*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007700:Kinetics; D007951:Leukemia, Myeloid; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
D000964:Antimetabolites, Antineoplastic; D006454:Hemoglobins; D012263:Ribonucleosides; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; C033706:tiazofurin