The effects of bestatin, a microbial aminopeptidase inhibitor, on epidermal growth factor-induced DNA synthesis and cell division in primary cultured hepatocytes of rats.
We investigated the effects of microbial protease inhibitors, in particular the aminopeptidase inhibitor bestatin, on DNA synthesis and cell division induced by epidermal growth factor (EGF) in hepatocytes. Although bestatin did not significantly affect binding of EGF to hepatocytes, it inhibited EGF-induced DNA synthesis and cell division. DNA synthesis in rat hepatocytes was maximal 24-26 h after EGF addition to the medium. The time required for maximal DNA synthesis was not affected if bestatin was removed less than 12 h after addition, but synthesis was partially inhibited if bestatin was added to the medium several hours after EGF addition, depending on the time of bestatin addition. Our results suggest that bestatin arrests the new cell cycle induced by EGF at about 12 h after the initiation. Considering also our results obtained by employing other protease inhibitors, we concluded that specific proteases play important roles in hepatocyte DNA synthesis and cell division induced by EGF.
Takahashi
S
S
Department of Agricultural Chemistry, Faculty of Agriculture, University of Tokyo, Japan.
Ohishi
Y
Y
Kato
H
H
Noguchi
T
T
Naito
H
H
Aoyagi
T
T
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism
D011480:Protease Inhibitors; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex; D013936:Thymidine