Temporal and spatial patterns of proto-oncogene expression at early stages of toxic liver injury in the rat.
Sequential and transient expression of c-fos, c-jun, c-myc, c-Ha-ras and c-Ki-ras proto-oncogene RNA transcripts with zonal heterogeneity was demonstrated in virtually all hepatocytes of adult rat liver by in situ hybridization with single-stranded, [35S]-labeled cRNA probes at various time points after intraperitoneal administration of a single dose of carbon tetrachloride (CCl4). After a brief interval, elevated RNA levels of these genes were also observed in nonparenchymal cells. A second phase of proto-oncogene expression was characterized by high RNA levels in only a fraction of parenchymal cells with preference of mediolobular areas. Distribution and number of these cells were comparable tl hepatocytes expressing the proliferation-associated nuclear antigen Ki-67 72 hours after toxic injury. Oncogene expression in the nonparenchymal compartment correlated with distinct morphologic changes preceding type I procollagen gene expression by desmin-positive perisinusoidal cells, accumulating together with numerous c-fms expressing cells in the areas of hepatocellular necrosis. We conclude that zonal hepatic destruction by carbon tetrachloride induces proto-oncogene expression with distinct temporal and spatial patterns initiated by the most severely damaged hepatocytes. Proto-oncogene products thus represent valuable markers of cellular activation preceding and accompanying various aspects of tissue repair reactions.
Herbst
H
H
Institute of Pathology, Klinikum Steglitz, Free University of Berlin, Germany.
Milani
S
S
Schuppan
D
D
Stein
H
H
D000818:Animals; D000911:Antibodies, Monoclonal; D002251:Carbon Tetrachloride / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury; D015870:Gene Expression; D007382:Intermediate Filaments / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008107:Liver Diseases / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011519:Proto-Oncogenes; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000911:Antibodies, Monoclonal; D011347:Procollagen; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D002251:Carbon Tetrachloride