Down-regulation of c-myc and c-Ha-ras gene expression by tiazofurin in rat hepatoma cells.
There was an overexpression of the c-myc gene (11-fold) and of the c-Ha-ras gene (2-fold) in rat hepatoma 3924A cells compared to normal rat liver as measured by dot-blot analysis of total cytoplasmic RNA. The overexpression of c-myc was attributed to a 10- to 14-fold amplification and rearrangement of the c-myc sequences as determined by Southern blot analysis. The expression of the c-myc also was dependent upon the proliferative state of the hepatoma cells. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide; NSC 286193), an inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of GTP biosynthesis, resulted in a rapid drop (less than 1 h) to 50% of control in the target enzyme activity in the hepatoma cells and in a subsequent marked decrease to 55% in GTP concentration. These events were followed at 12 h of tiazofurin treatment by a 3-fold reduction in the expression of the c-myc gene and a 9-fold decline in that of the c-Ha-ras gene. These results in the hepatoma cells provide evidence in support of the earlier demonstrated correlation in K562 cells between GTP concentration and expression of c-myc and c-ras genes (Olah et al., 1989). These genes might depend on GTP for their expression in hepatoma cells and they might cooperate in a signal pathway that controls cell proliferation.
Olah
E
E
Department of Molecular Biology, National Institute of Oncology, Budapest, Hungary.
Kote
Z
Z
Natsumeda
Y
Y
Yamaji
Y
Y
Jarai
G
G
Lapis
E
E
Financsek
I
I
Weber
G
G
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000235:genetics*; D005784:Gene Amplification / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D015321:Gene Rearrangement; D011905:Genes, ras / Q000187:drug effects* / Q000502:physiology; D006160:Guanosine Triphosphate / Q000378:metabolism; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012263:Ribonucleosides; D012254:Ribavirin; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D016283:Proto-Oncogene Proteins p21(ras); C033706:tiazofurin