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

E. Olah, Y. Natsumeda, T. Ikegami, Z. Kote, M. Horanyi, J. Szelenyi, E. Paulik, T. Kremmer, S. R. Hollan, J. Sugar, G. Weber

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Abstract

Tiazofurin (2-β-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 (<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)γ-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.

Original languageEnglish
Pages (from-to)6533-6537
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume85
Issue number17
DOIs
Publication statusPublished - Jan 1 1988

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