The G-C specific DNA binding drug, mithramycin, selectively inhibits transcription of the C-MYC and C-HA-RAS genes in regenerating liver.
Expression of the c-myc and c-Ha-ras protooncogenes is dramatically increased in regenerating rat liver as an early response to partial hepatectomy. Nuclear runon transcription studies confirm that the increased c-myc and c-Ha-ras mRNA levels in regenerating livers reflect transcriptional activation of these genes. Mithramycin, a G-C specific DNA binding drug, prevents the increased transcriptional activity of c-myc and c-Ha-ras genes after hepatectomy but does not alter the transcriptional activity of the beta-actin gene. Continuous exposure of rats to mithramycin after hepatectomy prevents the increase in both c-myc and c-Ha-ras expression and blocks the increased cellular proliferation characteristic of regeneration. The delayed increase in c-myc and c-Ha-ras gene expression is associated with a delay in cellular proliferation. The inhibition of c-myc and c-Ha-ras transcription by mithramycin, the delay in cellular proliferation, and the ability of mithramycin to prevent protein binding to the c-myc promoter, suggest that the increased expression of these genes is a necessary component of liver regeneration.
Campbell
V W
VW
Bolden Laboratory, Department of Internal Medicine, University of Alabama at Birmingham.
Davin
D
D
Thomas
S
S
Jones
D
D
Roesel
J
J
Tran-Patterson
R
R
Mayfield
C A
CA
Rodu
B
B
Miller
D M
DM
Hiramoto
R A
RA
D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D011905:Genes, ras; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration; D008926:Plicamycin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects*
D004247:DNA; D008926:Plicamycin