Tiazofurin induction of mouse erythroleukemia cell hemoglobin production in the absence of commitment or changes in protooncogene expression.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), is a synthetic nucleoside inhibitor of inosine monophosphate dehydrogenase and blocks guanine nucleotide biosynthesis. In the present study, we examined the effects of tiazofurin on mouse erythroleukemia (MEL) cell differentiation and protooncogene expression. Tiazofurin induced hemoglobin production in MEL cells in a concentration-dependent manner, as measured by an increase in benzidine staining. Northern blot analysis of MEL cells treated with 7 mumol/L tiazofurin demonstrated accumulation of both alpha- and beta-globin RNA transcripts. This induction of differentiation was blocked by the presence of exogenous guanosine (100 mumol/L). In contrast to the down-regulation of c-myc and c-myb RNA in MEL cells induced by dimethyl sulfoxide (DMSO) or hexamethylene bisacetamide (HMBA), there was no detectable change in levels of these transcripts after tiazofurin treatment. Furthermore, MEL cells induced by tiazofurin did not commit to terminal differentiation. These results suggest a role for guanine nucleotides, at least in part, in the regulation of MEL cell differentiation.
Sherman
M L
ML
Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Boston, MA 02115.
Shafman
T D
TD
Colman
M S
MS
Kufe
D W
DW
D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006454:Hemoglobins / Q000096:biosynthesis* / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011519:Proto-Oncogenes / Q000187:drug effects*; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D006454:Hemoglobins; D012263:Ribonucleosides; D012254:Ribavirin; C033706:tiazofurin; D004121:Dimethyl Sulfoxide