Impaired Hepatocyte DNA Synthetic Response Posthepatectomy in Insulin-like Growth Factor Binding Protein 1-deficient Mice with Defects in C/EBP Beta and Mitogen-activated Protein Kinase/extracellular Signal-regulated Kinase Regulation

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2003 Jan 31

PMID 12556485

Citations 37

Authors

Julia I. Leu

Mary Ann S Crissey

Linden E Craig

Rebecca Taub

Affiliations

Soon will be listed here.

Abstract

After a two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. One of the most rapidly and highly induced genes and proteins in regenerating liver is insulin-like growth factor binding protein 1 (IGFBP-1), a secreted protein that may modulate the activities of insulin-like growth factors (IGFs) or signal via IGF-independent mechanisms. To assess the functional role of IGFBP-1 in liver regeneration, mice with a targeted disruption of the IGFBP-1 gene were generated. Although IGFBP-1(-/-) mice demonstrated normal development, they had abnormal liver regeneration after partial hepatectomy, characterized by liver necrosis and reduced and delayed hepatocyte DNA synthesis. The abnormal regenerative response was associated with blunted activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and a reduced induction of C/EBP beta protein expression posthepatectomy. Like cell cycle abnormalities observed in hepatectomized C/EBP beta(-/-) mice, cyclin A and cyclin B1 expression was delayed and reduced in IGFBP-1(-/-) livers, whereas cyclin D1 expression was normal. Treatment of IGFBP-1(-/-) mice with a preoperative dose of IGFBP-1 induced MAPK/ERK activation and C/EBP beta expression, suggesting that IGFBP-1 may support liver regeneration at least in part via its effect on MAPK/ERK and C/EBP beta activities. These findings are the first demonstration of the involvement of IGFBP-1 in the regulation of in vivo mitogenic signaling pathways.

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References

Kondoh N, Wakatsuki T, Ryo A, Hada A, Aihara T, Horiuchi S . Identification and characterization of genes associated with human hepatocellular carcinogenesis. Cancer Res. 1999; 59(19):4990-6. View

Zimmermann J, Erdmann D, Lalande I, Grossenbacher R, Noorani M, Furst P . Proteasome inhibitor induced gene expression profiles reveal overexpression of transcriptional regulators ATF3, GADD153 and MAD1. Oncogene. 2000; 19(25):2913-20. DOI: 10.1038/sj.onc.1203606. View

Kim D, Lee D, Cho B, You K, Kim M, Ahn D . Down-regulation of insulin-like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid. Hepatology. 1999; 29(4):1091-8. DOI: 10.1002/hep.510290414. View

Yamada Y, Kirillova I, Peschon J, Fausto N . Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc Natl Acad Sci U S A. 1997; 94(4):1441-6. PMC: 19810. DOI: 10.1073/pnas.94.4.1441. View

TAUB R . Liver regeneration 4: transcriptional control of liver regeneration. FASEB J. 1996; 10(4):413-27. View

Akira S, Isshiki H, Sugita T, TANABE O, Kinoshita S, Nishio Y . A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990; 9(6):1897-906. PMC: 551896. DOI: 10.1002/j.1460-2075.1990.tb08316.x. View

Trembley J, Kren B, Steer C . Posttranscriptional regulation of cyclin B messenger RNA expression in the regenerating rat liver. Cell Growth Differ. 1994; 5(1):99-108. View

Zindy F, Lamas E, Chenivesse X, Sobczak J, Wang J, Fesquet D . Cyclin A is required in S phase in normal epithelial cells. Biochem Biophys Res Commun. 1992; 182(3):1144-54. DOI: 10.1016/0006-291x(92)91851-g. View

Poli V, Mancini F, Cortese R . IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell. 1990; 63(3):643-53. DOI: 10.1016/0092-8674(90)90459-r. View

10.

Mohn K, Melby A, Tewari D, Laz T, TAUB R . The gene encoding rat insulinlike growth factor-binding protein 1 is rapidly and highly induced in regenerating liver. Mol Cell Biol. 1991; 11(3):1393-401. PMC: 369411. DOI: 10.1128/mcb.11.3.1393-1401.1991. View

11.

Haber B, Naji L, Cressman D, TAUB R . Coexpression of liver-specific and growth-induced genes in perinatal and regenerating liver: attainment and maintenance of the differentiated state during rapid proliferation. Hepatology. 1995; 22(3):906-14. View

12.

Li W, Liang X, Leu J, Kovalovich K, Ciliberto G, TAUB R . Global changes in interleukin-6-dependent gene expression patterns in mouse livers after partial hepatectomy. Hepatology. 2001; 33(6):1377-86. DOI: 10.1053/jhep.2001.24431. View

13.

Lee J, Greenbaum L, Haber B, Nagle D, Lee V, Miles V . Structure and localization of the IGFBP-1 gene and its expression during liver regeneration. Hepatology. 1994; 19(3):656-65. DOI: 10.1002/hep.1840190317. View

14.

Factor V, Jensen M, Thorgeirsson S . Coexpression of C-myc and transforming growth factor alfa in the liver promotes early replicative senescence and diminishes regenerative capacity after partial hepatectomy in transgenic mice. Hepatology. 1997; 26(6):1434-43. DOI: 10.1002/hep.510260610. View

15.

Greenbaum L, Cressman D, Haber B, TAUB R . Coexistence of C/EBP alpha, beta, growth-induced proteins and DNA synthesis in hepatocytes during liver regeneration. Implications for maintenance of the differentiated state during liver growth. J Clin Invest. 1995; 96(3):1351-65. PMC: 185757. DOI: 10.1172/JCI118170. View

16.

Wang N, Finegold M, Bradley A, Ou C, Abdelsayed S, Wilde M . Impaired energy homeostasis in C/EBP alpha knockout mice. Science. 1995; 269(5227):1108-12. DOI: 10.1126/science.7652557. View

17.

Kovalovich K, Li W, DeAngelis R, Greenbaum L, Ciliberto G, TAUB R . Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem. 2001; 276(28):26605-13. DOI: 10.1074/jbc.M100740200. View

18.

Loyer P, Cariou S, Glaise D, Bilodeau M, Baffet G, Guguen-Guillouzo C . Growth factor dependence of progression through G1 and S phases of adult rat hepatocytes in vitro. Evidence of a mitogen restriction point in mid-late G1. J Biol Chem. 1996; 271(19):11484-92. DOI: 10.1074/jbc.271.19.11484. View

19.

Buck M, Poli V, Hunter T, Chojkier M . C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell. 2001; 8(4):807-16. DOI: 10.1016/s1097-2765(01)00374-4. View

20.

Tybulewicz V, Crawford C, Jackson P, Bronson R, Mulligan R . Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991; 65(7):1153-63. DOI: 10.1016/0092-8674(91)90011-m. View