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PMID: 9034332 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes.

The EMBO journal ·Vol. 16 ·No. 3 ·1997-02-03 ·Pages 495-503

Amicone L, Spagnoli FM, Späth G, Giordano S, Tommasini C, Bernardini S, De Luca V, Della Rocca C, Weiss MC, Comoglio PM, Tripodi M

Abstract

Hepatocyte growth factor induces proliferation, motility and differentiation of epithelial cells through the tyrosine kinase receptor encoded by the MET protooncogene. The cytoplasmic portion of Met (referred to as cyto-Met) is activated but only weakly transforming. In order to determine the effect of activated Met on hepatocytes, we have targeted truncated Met expression to the liver by incorporating the cDNA into a vector carrying the entire human alpha-1-antitrypsin transcriptional unit. Transgenic expression in the liver of truncated human Met, containing the regulatory and the catalytic cytoplasmic domains, renders hepatocytes constitutively resistant to apoptosis and reproducibly permits immortalization. The emerging stable cell lines are not transformed and maintain a highly differentiated phenotype judged by the retention of epithelial cell polarity and the expression of hepatocyte-enriched transcription factors as well as hepatic products.

MeSH Terms
Animals Antibodies, Monoclonal/immunology,metabolism,pharmacology Apoptosis/genetics,physiology Blotting, Northern Blotting, Southern Blotting, Western Cell Differentiation/genetics Cells, Cultured Gene Expression Regulation, Developmental/genetics Hepatocyte Growth Factor/metabolism Histocytochemistry Humans Immunohistochemistry Liver/metabolism Mice Mice, Transgenic Microscopy, Electron Proto-Oncogenes/genetics Receptor Protein-Tyrosine Kinases/genetics Transgenes/genetics alpha 1-Antitrypsin/genetics
Chemicals
Antibodies, Monoclonal alpha 1-Antitrypsin Hepatocyte Growth Factor Receptor Protein-Tyrosine Kinases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Amicone L
Dipartimento di Biopatologia Umana, Università La Sapienza, Roma, Italy.
Spagnoli F M
Späth G
Giordano S
Tommasini C
Bernardini S
De Luca V
Della Rocca C
Weiss M C
Comoglio P M
Tripodi M
References (44)
44 references, click to expand
  1. Chronic myelomonocytic leukemia: Tel-a-kinase what Ets all about.
    Cell. 1994 Apr 22;77(2):171-3 PMID: 8168126
  2. Temporal and tissue-specific expression of the MET ORF driven by the complete transcriptional unit of human A1AT gene in transgenic mice.
    Gene. 1995 Sep 11;162(2):323-8 PMID: 7557452
  3. Structural and functional domains critical for constitutive activation of the HGF-receptor (Met).
    Oncogene. 1994 Jun;9(6):1691-7 PMID: 8183564
  4. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us.
    Cell. 1994 Jun 3;77(5):627-38 PMID: 8205613
  5. Autonomous growth in serum-free medium and production of hepatocellular carcinomas by differentiated hepatocyte lines that overexpress transforming growth factor alpha 1.
    Cancer Res. 1994 Nov 15;54(22):5964-73 PMID: 7525051
  6. Fas-mediated apoptosis in primary cultured mouse hepatocytes.
    Exp Cell Res. 1994 Dec;215(2):332-7 PMID: 7526995
  7. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity.
    Cell. 1995 Jan 27;80(2):279-84 PMID: 7834747
  8. The rat serum albumin gene: analysis of cloned sequences.
    Proc Natl Acad Sci U S A. 1979 Jul;76(7):3256-60 PMID: 158758
  9. Expression of fetal and neonatal hepatic functions by mouse hepatoma-rat hepatoma hybrids.
    Somatic Cell Genet. 1979 Nov;5(6):719-38 PMID: 545721
  10. Molecular cloning of a new transforming gene from a chemically transformed human cell line.
    Nature. 1984 Sep 6-11;311(5981):29-33 PMID: 6590967
  11. Mechanism of met oncogene activation.
    Cell. 1986 Jun 20;45(6):895-904 PMID: 2423252
  12. Molecular cloning of cDNA for rat liver gap junction protein.
    J Cell Biol. 1986 Jul;103(1):123-34 PMID: 3013898
  13. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia.
    J Cell Biol. 1986 Sep;103(3):755-66 PMID: 3528172
  14. Purification and characterization of a growth factor from rat platelets for mature parenchymal hepatocytes in primary cultures.
    Proc Natl Acad Sci U S A. 1986 Sep;83(17):6489-93 PMID: 3529086
  15. The human alpha-1-antitrypsin gene is efficiently expressed from two tissue-specific promotors in transgenic mice.
    Nucleic Acids Res. 1987 Sep 25;15(18):7519-29 PMID: 3498933
  16. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.
    Nature. 1988 Sep 29;335(6189):440-2 PMID: 3262202
  17. Isolation of a recombinant copy of the gene encoding C/EBP.
    Genes Dev. 1988 Jul;2(7):786-800 PMID: 2850264
  18. Tyrosine kinase receptor indistinguishable from the c-met protein.
    Nature. 1989 May 11;339(6220):155-6 PMID: 2541345
  19. The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA binding domain.
    Cell. 1989 Oct 6;59(1):145-57 PMID: 2571419
  20. Liver regeneration: molecular mechanisms of growth control.
    FASEB J. 1990 Feb 1;4(2):176-87 PMID: 2404819
  21. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines.
    J Immunol. 1990 May 1;144(9):3602-10 PMID: 2184193
  22. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells.
    J Cell Biol. 1990 Nov;111(5 Pt 1):2097-108 PMID: 2146276
  23. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.
    Nature. 1990 Nov 22;348(6299):334-6 PMID: 2250705
  24. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor.
    Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):415-9 PMID: 1824873
  25. Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily.
    Genes Dev. 1990 Dec;4(12B):2353-65 PMID: 2279702
  26. LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia.
    EMBO J. 1991 Jun;10(6):1435-43 PMID: 1673925
  27. Epithelial scatter factor and development of the chick embryonic axis.
    Development. 1990 Dec;110(4):1271-84 PMID: 2151613
  28. A role for both RB and p53 in the regulation of human cellular senescence.
    Exp Cell Res. 1991 Sep;196(1):33-9 PMID: 1652450
  29. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
    Genes Dev. 1991 Sep;5(9):1538-52 PMID: 1840554
  30. Gene expression in hepatocyte-like lines established by targeted carcinogenesis in transgenic mice.
    Exp Cell Res. 1992 May;200(1):175-85 PMID: 1373387
  31. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth.
    J Cell Biol. 1992 Nov;119(3):629-41 PMID: 1383237
  32. Transfer of motogenic and invasive response to scatter factor/hepatocyte growth factor by transfection of human MET protooncogene.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):649-53 PMID: 8380644
  33. The presence of hepatocyte growth factor in the developing rat.
    Development. 1992 Oct;116(2):387-95 PMID: 1286614
  34. An ion-transporting ATPase encodes multiple apical localization signals.
    J Cell Biol. 1993 Apr;121(2):283-93 PMID: 8385670
  35. A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor.
    Mol Cell Biol. 1993 Aug;13(8):4600-8 PMID: 7687741
  36. Lethal effect of the anti-Fas antibody in mice.
    Nature. 1993 Aug 26;364(6440):806-9 PMID: 7689176
  37. Programmed cell death and the control of cell survival: lessons from the nervous system.
    Science. 1993 Oct 29;262(5134):695-700 PMID: 8235590
  38. Enhanced proliferative potential in culture of cells from p53-deficient mice.
    Oncogene. 1993 Dec;8(12):3313-22 PMID: 7504233
  39. Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha.
    Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):674-8 PMID: 7904757
  40. Disruption of epithelial cell-matrix interactions induces apoptosis.
    J Cell Biol. 1994 Feb;124(4):619-26 PMID: 8106557
  41. Scatter factor/hepatocyte growth factor is essential for liver development.
    Nature. 1995 Feb 23;373(6516):699-702 PMID: 7854452
  42. Receptor protein-tyrosine kinases and their signal transduction pathways.
    Annu Rev Cell Biol. 1994;10:251-337 PMID: 7888178
  43. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor.
    Science. 1995 Mar 31;267(5206):2003-6 PMID: 7701324
  44. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.
    Cell. 1994 Apr 22;77(2):261-71 PMID: 7513258
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.3.495
Published
1997-02-03
Pages
495-503
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1169653
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/16.3.495 PMC Full Text View journal details
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