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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Apr 1993; 91(4): 1319–1326.
PMCID: PMC288102

Induction patterns of 70 genes during nine days after hepatectomy define the temporal course of liver regeneration.

Abstract

Liver regeneration is an important process that allows for recovery from hepatic injuries caused by viruses, toxins, ischemia, surgery, and transplantation. Previously, we identified > 70 immediate-early genes induced in regenerating liver after hepatectomy, 41 of which were novel. While it is expected that the proteins encoded by these genes may have important roles in regulating progression through the G1 phase of the cell cycle during regeneration, we were surprised to note that many of these "early" genes are expressed for extended periods during the hepatic growth response. Here we define several patterns of expression of immediate-early, delayed-early, and liver-specific genes during the 9-d period after hepatectomy. One pattern of induction parallels the major growth period of the liver that ends at 60-72 h after hepatectomy. A second pattern has two peaks coincident with the first and second G1 phases of the two hepatic cell cycles. A third group, which includes liver-specific genes such as C/EBP alpha, shows maximal expression after the growth period. Although the peak in DNA synthesis in nonparenchymal cells occur 24 h later than in hepatocytes, most of the genes studied demonstrate similar induction in both cell types. This finding suggests that the G0/G1 transition occurs simultaneously in all cells in the liver, but that the G1 phase of nonparenchymal cells may be relatively prolonged. Finally, we examined the expression of > 70 genes in clinical settings that could induce liver regeneration, including after perfusion in a donor liver, hepatic ischemia, and fulminant hepatic failure. We found that a small number of early and liver-specific genes were selectively activated in human livers under these conditions, and we thereby provide a potential means of measuring the caliber of the regenerative response in clinical situations.

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Selected References

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  • Fausto N, Mead JE. Regulation of liver growth: protooncogenes and transforming growth factors. Lab Invest. 1989 Jan;60(1):4–13. [PubMed]
  • Michalopoulos GK. Liver regeneration: molecular mechanisms of growth control. FASEB J. 1990 Feb 1;4(2):176–187. [PubMed]
  • Bucher NL, Swaffield MN. Synergistic action of glucagon and insulin in regulation of hepatic regeneration. Adv Enzyme Regul. 1975;13:281–293. [PubMed]
  • GRISHAM JW. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res. 1962 Aug;22:842–849. [PubMed]
  • Cochran BH, Reffel AC, Stiles CD. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell. 1983 Jul;33(3):939–947. [PubMed]
  • Lau LF, Nathans D. Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J. 1985 Dec 1;4(12):3145–3151. [PMC free article] [PubMed]
  • Lau LF, Nathans D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182–1186. [PMC free article] [PubMed]
  • Lim RW, Varnum BC, Herschman HR. Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene. 1987;1(3):263–270. [PubMed]
  • Almendral JM, Sommer D, Macdonald-Bravo H, Burckhardt J, Perera J, Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol. 1988 May;8(5):2140–2148. [PMC free article] [PubMed]
  • Zipfel PF, Irving SG, Kelly K, Siebenlist U. Complexity of the primary genetic response to mitogenic activation of human T cells. Mol Cell Biol. 1989 Mar;9(3):1041–1048. [PMC free article] [PubMed]
  • Herschman HR. Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem. 1991;60:281–319. [PubMed]
  • Kruijer W, Skelly H, Botteri F, van der Putten H, Barber JR, Verma IM, Leffert HL. Proto-oncogene expression in regenerating liver is simulated in cultures of primary adult rat hepatocytes. J Biol Chem. 1986 Jun 15;261(17):7929–7933. [PubMed]
  • Mohn KL, Laz TM, Melby AE, Taub R. Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. J Biol Chem. 1990 Dec 15;265(35):21914–21921. [PubMed]
  • Mohn KL, Laz TM, Hsu JC, Melby AE, Bravo R, Taub R. The immediate-early growth response in regenerating liver and insulin-stimulated H-35 cells: comparison with serum-stimulated 3T3 cells and identification of 41 novel immediate-early genes. Mol Cell Biol. 1991 Jan;11(1):381–390. [PMC free article] [PubMed]
  • Taub R, Roy A, Dieter R, Koontz J. Insulin as a growth factor in rat hepatoma cells. Stimulation of proto-oncogene expression. J Biol Chem. 1987 Aug 5;262(22):10893–10897. [PubMed]
  • Jamieson NV. Review article: improved preservation of the liver for transplantation. Aliment Pharmacol Ther. 1991 Apr;5(2):91–104. [PubMed]
  • Gores GJ, Kost LJ, LaRusso NF. The isolated perfused rat liver: conceptual and practical considerations. Hepatology. 1986 May-Jun;6(3):511–517. [PubMed]
  • Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol. 1976;13:29–83. [PubMed]
  • Wolkoff AW, Johansen KL, Goeser T. The isolated perfused rat liver: preparation and application. Anal Biochem. 1987 Nov 15;167(1):1–14. [PubMed]
  • Hendriks HF, Brouwer A, Knook DL. Isolation, purification, and characterization of liver cell types. Methods Enzymol. 1990;190:49–58. [PubMed]
  • Mohn KL, Melby AE, Tewari DS, Laz TM, Taub R. The gene encoding rat insulinlike growth factor-binding protein 1 is rapidly and highly induced in regenerating liver. Mol Cell Biol. 1991 Mar;11(3):1393–1401. [PMC free article] [PubMed]
  • Birkenmeier EH, Gwynn B, Howard S, Jerry J, Gordon JI, Landschulz WH, McKnight SL. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 1989 Aug;3(8):1146–1156. [PubMed]
  • Mischoulon D, Rana B, Bucher NL, Farmer SR. Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture. Mol Cell Biol. 1992 Jun;12(6):2553–2560. [PMC free article] [PubMed]
  • Sukhatme VP, Kartha S, Toback FG, Taub R, Hoover RG, Tsai-Morris CH. A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. Oncogene Res. 1987 Sep-Oct;1(4):343–355. [PubMed]
  • Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991 Jan 18;251(4991):288–292. [PubMed]
  • Knook DL, Blansjaar N, Sleyster EC. Isolation and characterization of Kupffer and endothelial cells from the rat liver. Exp Cell Res. 1977 Oct 15;109(2):317–329. [PubMed]
  • Alcorn JA, Feitelberg SP, Brenner DA. Transient induction of c-jun during hepatic regeneration. Hepatology. 1990 Jun;11(6):909–915. [PubMed]
  • Hsu JC, Laz T, Mohn KL, Taub R. Identification of LRF-1, a leucine-zipper protein that is rapidly and highly induced in regenerating liver. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3511–3515. [PMC free article] [PubMed]
  • Hsu JC, Bravo R, Taub R. Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration. Mol Cell Biol. 1992 Oct;12(10):4654–4665. [PMC free article] [PubMed]
  • Christy RJ, Kaestner KH, Geiman DE, Lane MD. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2593–2597. [PMC free article] [PubMed]
  • Charles CH, Simske JS, O'Brien TP, Lau LF. Pip92: a short-lived, growth factor-inducible protein in BALB/c 3T3 and PC12 cells. Mol Cell Biol. 1990 Dec;10(12):6769–6774. [PMC free article] [PubMed]
  • Charles CH, Abler AS, Lau LF. cDNA sequence of a growth factor-inducible immediate early gene and characterization of its encoded protein. Oncogene. 1992 Jan;7(1):187–190. [PubMed]

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