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. 1988 Sep;85(17):6533–6537. doi: 10.1073/pnas.85.17.6533

Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 leukemia cells.

E Olah 1, Y Natsumeda 1, T Ikegami 1, Z Kote 1, M Horanyi 1, J Szelenyi 1, E Paulik 1, T Kremmer 1, S R Hollan 1, J Sugar 1, et al.
PMCID: PMC282007  PMID: 2901100

Abstract

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.

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