ABSTRACT
Exposure to X radiation is associated with a decline in the proliferative activity of the liver, but the molecular mechanism(s) is not well understood. We investigated whether exposure to X radiation is involved in functional changes in the epidermal growth factor (EGF) receptor (EGFR), thereby causing a reduction of EGF-induced DNA synthesis using periportal hepatocytes (PPH) and perivenous hepatocytes (PVH), which differ in their proliferative activity. X radiation dose-dependently decreased DNA synthesis in both subpopulations. The rate of decline in the DNA synthesis was greater in PPH than in PVH, but the zonal difference disappeared after exposure to 10 Gy X radiation. [(125)I]EGF binding studies indicated that high-affinity EGFRs in both subpopulations were down-regulated after X irradiation. Furthermore, EGF-induced EGFR dimerization and phosphorylation at Y1173 in both subpopulations were down-regulated after X irradiation, and the rate of decline was greater in PPH than in PVH. In contrast, phosphorylation at Y845 after EGF treatment was dose-dependently up-regulated after X irradiation in both subpopulations. These results suggest that the X-radiation-related decline in EGF-induced DNA synthesis is caused at least partly by the modification of EGFR function.
Subject(s)
Down-Regulation/radiation effects , ErbB Receptors/metabolism , Hepatocytes/radiation effects , Animals , Cells, Cultured , DNA Replication/radiation effects , Dimerization , Dose-Response Relationship, Radiation , Hepatocytes/cytology , Hepatocytes/metabolism , Male , Phosphorylation , Rats , Rats, Wistar , X-RaysABSTRACT
Liver regeneration is regulated by several factors, including growth factors, cytokines, and post-translational modifications of several proteins. It is suggested that transglutaminase 2 (TG2) and ornithine decarboxylase (ODC) are involved in liver regeneration. To investigate the role of TG2 and ODC activities in regenerating liver, we used retinoic acid (RA), an inducer of TG2 and a suppressor of ODC. Regenerating rat liver was prepared by 70% partial hepatectomy (PH). Rats were sacrificed at 1, 2, 3, 4, and 6 days after surgery. RA was intraperitoneally injected immediately after PH. TG2 and ODC activities and products (epsilon-(gamma-glutamyl) lysine isopeptide (Gln-Lys) and polyamines, respectively) were examined at the indicated times. In RA-treated rat, DNA synthesis and ODC activity declined and the peak shifted to 2 days after PH, whereas TG2 activity increased at 1 day after PH. At that time, protein-polyamine, especially the protein-spermidine (SPD) bond, transiently decreased, whereas the formation of the Gln-Lys bond increased after PH. These results suggested that in regenerating liver, enhanced the formation of Gln-Lys bonds catalyzed by TG2 led to reduced DNA synthesis, whereas when ODC produced newly synthesized SPD, the inhibition of Gln-Lys bond production by the preferential formation of protein-SPD bonds led to an increase in DNA synthesis.
Subject(s)
GTP-Binding Proteins/metabolism , Liver Regeneration/drug effects , Ornithine Decarboxylase/metabolism , Transglutaminases/metabolism , Tretinoin/pharmacology , Animals , DNA/biosynthesis , Enzyme Induction/drug effects , Flow Cytometry , GTP-Binding Proteins/biosynthesis , Hepatectomy , Liver/drug effects , Liver/enzymology , Male , Ornithine Decarboxylase/biosynthesis , Polyamines/metabolism , Protein Glutamine gamma Glutamyltransferase 2 , Rats , Rats, Wistar , Time Factors , Transglutaminases/biosynthesisABSTRACT
As (67)Ga is injected into the blood, (67)Ga is immediately bound to transferrin (Tf) and transported to various tissues and the Tf-(67)Ga complex binds to Tf receptor on various tissues. In partial hepatectomy (PH) a part of blood in circulation is lost together with removed liver tissues, consequently the amounts of blood cells and Tf in circulation decrease. In order to investigate the effect of those decreases on (67)Ga uptake by the liver, we compared the uptake in partially hepatectomized rats with that in venesectioned rats in which only a part of blood in circulation decreased. A two-thirds PH was performed. Two milliliters of blood was venesectioned. Each treated rat was intraveneously injected with (67)Ga. The changes of erythrocyte and reticulocyte contents after PH did not differ from those after venesection (VS) at all. But (67)Ga uptake by reticulocytes significantly increased after VS but did not after PH. On the other hand, (67)Ga uptake by the liver significantly increased after PH but did not after VS. These differences must be related to the different expression of Tf receptors on the liver after PH and VS.
