Induction of replicative competence ("priming") in normal liver.
We have used a system of nutritional manipulation to investigate whether hepatocytes of the normal liver can be primed for replication in vivo. In this system, rats that are denied protein for 3 days undergo a burst of hepatic DNA synthesis and mitosis when they are refed amino acids, while normally fed or starved rats do not respond. To determine if hepatocytes of protein deprived (PD) rats have been "primed" for replication, we examined changes in protooncogene expression in livers of PD rats to see if they would mimic the pattern of gene expression that is induced early after partial hepatectomy. c-jun, c-myc, and p53 mRNAs were elevated in livers of PD rats, while c-fos and c-ras genes were not expressed. The administration of amino acids to PD rats stimulated hepatic DNA synthesis in a shorter period than is required after partial hepatectomy and induced p53 and c-ras expression. In culture, hepatocytes from PD rats had higher levels of c-myc mRNA, underwent morphological changes more rapidly, and reached maximum rates of DNA synthesis earlier than normal hepatocytes. In both normal and primed hepatocyte cultures, transforming growth factor alpha stimulated DNA synthesis more effectively than epidermal growth factor. We conclude that hepatocytes pass through a priming stage before they proliferate and that replicative competence without DNA synthesis can be induced in hepatocytes in the normal liver.
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912.
J E
JE
Mead
L
L
Braun
D A
DA
Martin
N
N
Fausto
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D004044:Dietary Proteins / Q000235:genetics / Q000494:pharmacology; D015870:Gene Expression; D006133:Growth Substances / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008938:Mitosis / Q000502:physiology; D011488:Protein Deficiency / Q000235:genetics / Q000473:pathology; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D000596:Amino Acids; D004044:Dietary Proteins; D006133:Growth Substances; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004247:DNA