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Proc Natl Acad Sci U S A. Aug 29, 1995; 92(18): 8483–8487.
PMCID: PMC41181

Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals.

Abstract

Apolipoprotein (apo-) B mRNA editing is the deamination of cytidine that creates a new termination codon and produces a truncated version of apo-B (apo-B48). The cytidine deaminase catalytic subunit [apo-B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1)] of the multiprotein editing complex has been identified. We generated transgenic rabbits and mice expressing rabbit APOBEC-1 in their livers to determine whether hepatic expression would lower low density lipoprotein cholesterol concentrations. The apo-B mRNA from the livers of the transgenic mice and rabbit was extensively edited, and the transgenic animals had reduced concentrations of apo-B100 and low density lipoproteins compared with control animals. Unexpectedly, all of the transgenic mice and a transgenic rabbit had liver dysplasia, and many transgenic mice developed hepatocellular carcinomas. Many of the mouse livers were hyperplastic and filled with lipid. Other hepatic mRNAs with sequence motifs similar to apo-B mRNA were examined for this type of editing (i.e., cytidine deamination). One of these, tyrosine kinase, was edited in livers of transgenic mice but not of controls. This result demonstrates that other mRNAs can be edited by the overexpressed editing enzyme and suggests that aberrant editing of hepatic mRNAs involved in cell growth and regulation is the cause of the tumorigenesis. Finally, these findings compromise the potential use of APOBEC-1 for gene therapy to lower plasma levels of low density lipoproteins.

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  • Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987 Sep 11;50(6):831–840. [PubMed]
  • Chen SH, Habib G, Yang CY, Gu ZW, Lee BR, Weng SA, Silberman SR, Cai SJ, Deslypere JP, Rosseneu M, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987 Oct 16;238(4825):363–366. [PubMed]
  • Young SG. Recent progress in understanding apolipoprotein B. Circulation. 1990 Nov;82(5):1574–1594. [PubMed]
  • Yao Z, McLeod RS. Synthesis and secretion of hepatic apolipoprotein B-containing lipoproteins. Biochim Biophys Acta. 1994 May 13;1212(2):152–166. [PubMed]
  • Greeve J, Altkemper I, Dieterich JH, Greten H, Windler E. Apolipoprotein B mRNA editing in 12 different mammalian species: hepatic expression is reflected in low concentrations of apoB-containing plasma lipoproteins. J Lipid Res. 1993 Aug;34(8):1367–1383. [PubMed]
  • Teng B, Blumenthal S, Forte T, Navaratnam N, Scott J, Gotto AM, Jr, Chan L. Adenovirus-mediated gene transfer of rat apolipoprotein B mRNA-editing protein in mice virtually eliminates apolipoprotein B-100 and normal low density lipoprotein production. J Biol Chem. 1994 Nov 25;269(47):29395–29404. [PubMed]
  • Driscoll DM, Lakhe-Reddy S, Oleksa LM, Martinez D. Induction of RNA editing at heterologous sites by sequences in apolipoprotein B mRNA. Mol Cell Biol. 1993 Dec;13(12):7288–7294. [PMC free article] [PubMed]
  • Boström K, Garcia Z, Poksay KS, Johnson DF, Lusis AJ, Innerarity TL. Apolipoprotein B mRNA editing. Direct determination of the edited base and occurrence in non-apolipoprotein B-producing cell lines. J Biol Chem. 1990 Dec 25;265(36):22446–22452. [PubMed]
  • Hadjiagapiou C, Giannoni F, Funahashi T, Skarosi SF, Davidson NO. Molecular cloning of a human small intestinal apolipoprotein B mRNA editing protein. Nucleic Acids Res. 1994 May 25;22(10):1874–1879. [PMC free article] [PubMed]
  • Funahashi T, Giannoni F, DePaoli AM, Skarosi SF, Davidson NO. Tissue-specific, developmental and nutritional regulation of the gene encoding the catalytic subunit of the rat apolipoprotein B mRNA editing enzyme: functional role in the modulation of apoB mRNA editing. J Lipid Res. 1995 Mar;36(3):414–428. [PubMed]
  • Teng B, Burant CF, Davidson NO. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science. 1993 Jun 18;260(5115):1816–1819. [PubMed]
  • Harris SG, Sabio I, Mayer E, Steinberg MF, Backus JW, Sparks JD, Sparks CE, Smith HC. Extract-specific heterogeneity in high-order complexes containing apolipoprotein B mRNA editing activity and RNA-binding proteins. J Biol Chem. 1993 Apr 5;268(10):7382–7392. [PubMed]
  • Giannoni F, Bonen DK, Funahashi T, Hadjiagapiou C, Burant CF, Davidson NO. Complementation of apolipoprotein B mRNA editing by human liver accompanied by secretion of apolipoprotein B48. J Biol Chem. 1994 Feb 25;269(8):5932–5936. [PubMed]
  • Driscoll DM, Zhang Q. Expression and characterization of p27, the catalytic subunit of the apolipoprotein B mRNA editing enzyme. J Biol Chem. 1994 Aug 5;269(31):19843–19847. [PubMed]
  • Yamanaka S, Poksay KS, Balestra ME, Zeng GQ, Innerarity TL. Cloning and mutagenesis of the rabbit ApoB mRNA editing protein. A zinc motif is essential for catalytic activity, and noncatalytic auxiliary factor(s) of the editing complex are widely distributed. J Biol Chem. 1994 Aug 26;269(34):21725–21734. [PubMed]
  • Fan J, Wang J, Bensadoun A, Lauer SJ, Dang Q, Mahley RW, Taylor JM. Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8724–8728. [PMC free article] [PubMed]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [PMC free article] [PubMed]
  • Maronpot RR, Montgomery CA, Jr, Boorman GA, McConnell EE. National Toxicology Program nomenclature for hepatoproliferative lesions of rats. Toxicol Pathol. 1986;14(2):263–273. [PubMed]
  • Shah RR, Knott TJ, Legros JE, Navaratnam N, Greeve JC, Scott J. Sequence requirements for the editing of apolipoprotein B mRNA. J Biol Chem. 1991 Sep 5;266(25):16301–16304. [PubMed]
  • Backus JW, Schock D, Smith HC. Only cytidines 5' of the apolipoprotein B mRNA mooring sequence are edited. Biochim Biophys Acta. 1994 Sep 13;1219(1):1–14. [PubMed]
  • Pearson WR, Lipman DJ. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. [PMC free article] [PubMed]
  • Paulauskis JD, Sul HS. Structure of mouse fatty acid synthase mRNA. Identification of the two NADPH binding sites. Biochem Biophys Res Commun. 1989 Feb 15;158(3):690–695. [PubMed]
  • Thömmes P, Fett R, Schray B, Burkhart R, Barnes M, Kennedy C, Brown NC, Knippers R. Properties of the nuclear P1 protein, a mammalian homologue of the yeast Mcm3 replication protein. Nucleic Acids Res. 1992 Mar 11;20(5):1069–1074. [PMC free article] [PubMed]
  • Abachi S, Baringer P, Bylsma BG, DeBonte R, Koltick D, Loeffler FJ, Low EH, McIlwain RL, Miller DH, Ng CR, et al. Observation of tensor and scalar mesons produced in e+e- annihilation at 29 GeV. Phys Rev Lett. 1986 Oct 20;57(16):1990–1993. [PubMed]
  • Mano H, Ishikawa F, Nishida J, Hirai H, Takaku F. A novel protein-tyrosine kinase, tec, is preferentially expressed in liver. Oncogene. 1990 Dec;5(12):1781–1786. [PubMed]
  • Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991 Jul 15;266(20):12866–12872. [PubMed]
  • Sharma PM, Bowman M, Madden SL, Rauscher FJ, 3rd, Sukumar S. RNA editing in the Wilms' tumor susceptibility gene, WT1. Genes Dev. 1994 Mar 15;8(6):720–731. [PubMed]

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