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. 1997 Sep 1;326(Pt 2):311–320. doi: 10.1042/bj3260311

A specific distal promoter controls gamma-glutamyl transpeptidase gene expression in undifferentiated rat transformed liver cells.

S Nomura 1, O Lahuna 1, T Suzuki 1, A Brouillet 1, M N Chobert 1, Y Laperche 1
PMCID: PMC1218671  PMID: 9291098

Abstract

In rat undifferentiated hepatoma cells, the gamma-glutamyl transpeptidase (GGT) gene is transcribed into a 2.3 and a 2.6 kb mRNA which, in contrast with other rat GGT transcripts, are not detected in more differentiated liver cells or adult tissues. Analysis of the cDNA sequences obtained from H5 hepatoma cells reveals that these two transcripts differ from other GGT mRNAs by a 312-nt unique untranslated leader sequence; this sequence maps on the gene in a single exon 10 kb upstream from the GGT promoter IV transcription start site. We established that the 2.6 kb mRNA V-1 and the 2.3 kb GGT mRNA V-2 derive, by alternate splicing, from a primary transcript initiated on a distal promoter on the rat GGT gene. This gene appears to be transcribed from five promoters, and the specific expression of this new distal promoter in undifferentiated hepatoma cells requires binding of activator protein-1 and hepatic nuclear factor 3 specific transcription factors to a composite cis-element in the proximal region of the promoter. The distal GGT promoter, specifically expressed in undifferentiated liver cells, might reflect the expression of that gene in liver precursor cells before they differentiate in the hepatocytic or biliary lineage.

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Selected References

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  1. Ayoubi T. A., Van De Ven W. J. Regulation of gene expression by alternative promoters. FASEB J. 1996 Mar;10(4):453–460. [PubMed] [Google Scholar]
  2. Brouillet A., Darbouy M., Okamoto T., Chobert M. N., Lahuna O., Garlatti M., Goodspeed D., Laperche Y. Functional characterization of the rat gamma-glutamyl transpeptidase promoter that is expressed and regulated in the liver and hepatoma cells. J Biol Chem. 1994 May 27;269(21):14878–14884. [PubMed] [Google Scholar]
  3. Chobert M. N., Lahuna O., Lebargy F., Kurauchi O., Darbouy M., Bernaudin J. F., Guellaen G., Barouki R., Laperche Y. Tissue-specific expression of two gamma-glutamyl transpeptidase mRNAs with alternative 5' ends encoded by a single copy gene in the rat. J Biol Chem. 1990 Feb 5;265(4):2352–2357. [PubMed] [Google Scholar]
  4. Costa R. H., Grayson D. R., Darnell J. E., Jr Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol. 1989 Apr;9(4):1415–1425. doi: 10.1128/mcb.9.4.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Darbouy M., Chobert M. N., Lahuna O., Okamoto T., Bonvalet J. P., Farman N., Laperche Y. Tissue-specific expression of multiple gamma-glutamyl transpeptidase mRNAs in rat epithelia. Am J Physiol. 1991 Dec;261(6 Pt 1):C1130–C1137. doi: 10.1152/ajpcell.1991.261.6.C1130. [DOI] [PubMed] [Google Scholar]
  6. Deschatrette J., Moore E. E., Dubois M., Weiss M. C. Dedifferentiated variants of a rat hepatoma:reversion analysis. Cell. 1980 Apr;19(4):1043–1051. doi: 10.1016/0092-8674(80)90095-1. [DOI] [PubMed] [Google Scholar]
  7. Frohman M. A., Dush M. K., Martin G. R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8998–9002. doi: 10.1073/pnas.85.23.8998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Garlatti M., Tchesnokov V., Daheshia M., Feilleux-Duché S., Hanoune J., Aggerbeck M., Barouki R. CCAAT/enhancer-binding protein-related proteins bind to the unusual promoter of the aspartate aminotransferase housekeeping gene. J Biol Chem. 1993 Mar 25;268(9):6567–6574. [PubMed] [Google Scholar]
  9. Gorman C. M., Merlino G. T., Willingham M. C., Pastan I., Howard B. H. The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6777–6781. doi: 10.1073/pnas.79.22.6777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grange T., Roux J., Rigaud G., Pictet R. Cell-type specific activity of two glucocorticoid responsive units of rat tyrosine aminotransferase gene is associated with multiple binding sites for C/EBP and a novel liver-specific nuclear factor. Nucleic Acids Res. 1991 Jan 11;19(1):131–139. doi: 10.1093/nar/19.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gregori C., Kahn A., Pichard A. L. Competition between transcription factors HNF1 and HNF3, and alternative cell-specific activation by DBP and C/EBP contribute to the regulation of the liver-specific aldolase B promoter. Nucleic Acids Res. 1993 Feb 25;21(4):897–903. doi: 10.1093/nar/21.4.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Griffiths S. A., Good V. M., Gordon L. A., Hudson E. A., Barrett M. C., Munks R. J., Manson M. M. Characterization of a promoter for gamma-glutamyl transpeptidase activated in rat liver in response to aflatoxin B1 and ethoxyquin. Mol Carcinog. 1995 Dec;14(4):251–262. doi: 10.1002/mc.2940140405. [DOI] [PubMed] [Google Scholar]
  13. Guan K. L., Weiner H. Influence of the 5'-end region of aldehyde dehydrogenase mRNA on translational efficiency. Potential secondary structure inhibition of translation in vitro. J Biol Chem. 1989 Oct 25;264(30):17764–17769. [PubMed] [Google Scholar]
  14. Habib G. M., Carter B. Z., Sepulveda A. R., Shi Z. Z., Wan D. F., Lebovitz R. M., Lieberman M. W. Identification of a sixth promoter that directs the transcription of gamma-glutamyl transpeptidase type III RNA in mouse. J Biol Chem. 1995 Jun 9;270(23):13711–13715. doi: 10.1074/jbc.270.23.13711. [DOI] [PubMed] [Google Scholar]
  15. Habib G. M., Rajagopalan S., Godwin A. K., Lebovitz R. M., Lieberman M. W. The same gamma-glutamyl transpeptidase RNA species is expressed in fetal liver, hepatic carcinomas, and rasT24-transformed rat liver epithelial cells. Mol Carcinog. 1992;5(1):75–80. doi: 10.1002/mc.2940050112. [DOI] [PubMed] [Google Scholar]
  16. Hanigan M. H., Pitot H. C. Gamma-glutamyl transpeptidase--its role in hepatocarcinogenesis. Carcinogenesis. 1985 Feb;6(2):165–172. doi: 10.1093/carcin/6.2.165. [DOI] [PubMed] [Google Scholar]
  17. Herbst R. S., Nielsch U., Sladek F., Lai E., Babiss L. E., Darnell J. E., Jr Differential regulation of hepatocyte-enriched transcription factors explains changes in albumin and transthyretin gene expression among hepatoma cells. New Biol. 1991 Mar;3(3):289–296. [PubMed] [Google Scholar]
  18. Hirai S., Yaniv M. Jun DNA-binding is modulated by mutations between the leucines or by direct interaction of fos with the TGACTCA sequence. New Biol. 1989 Nov;1(2):181–191. [PubMed] [Google Scholar]
  19. Huggett A. C., Ellis P. A., Ford C. P., Hampton L. L., Rimoldi D., Thorgeirsson S. S. Development of resistance to the growth inhibitory effects of transforming growth factor beta 1 during the spontaneous transformation of rat liver epithelial cells. Cancer Res. 1991 Nov 1;51(21):5929–5936. [PubMed] [Google Scholar]
  20. Iannaccone P. M., Koizumi J. Pattern and rate of disappearance of gamma-glutamyl transpeptidase activity in fetal and neonatal rat liver. J Histochem Cytochem. 1983 Nov;31(11):1312–1316. doi: 10.1177/31.11.6194205. [DOI] [PubMed] [Google Scholar]
  21. Jackson D. A., Rowader K. E., Stevens K., Jiang C., Milos P., Zaret K. S. Modulation of liver-specific transcription by interactions between hepatocyte nuclear factor 3 and nuclear factor 1 binding DNA in close apposition. Mol Cell Biol. 1993 Apr;13(4):2401–2410. doi: 10.1128/mcb.13.4.2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kuo C. J., Conley P. B., Chen L., Sladek F. M., Darnell J. E., Jr, Crabtree G. R. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. doi: 10.1038/355457a0. [DOI] [PubMed] [Google Scholar]
  23. Kurauchi O., Lahuna O., Darbouy M., Aggerbeck M., Chobert M. N., Laperche Y. Organization of the 5' end of the rat gamma-glutamyl transpeptidase gene: structure of a promoter active in the kidney. Biochemistry. 1991 Feb 12;30(6):1618–1623. doi: 10.1021/bi00220a025. [DOI] [PubMed] [Google Scholar]
  24. Lafarge-Frayssinet C., Estrade S., Rosa-Loridon B., Frayssinet C., Cassingena R. Expression of gamma-glutamyl transpeptidase in adult rat liver cells after transformation with SV40 virus. Cancer Lett. 1984 Feb;22(1):31–39. doi: 10.1016/0304-3835(84)90040-5. [DOI] [PubMed] [Google Scholar]
  25. Lahuna O., Brouillet A., Chobert M. N., Darbouy M., Okamoto T., Laperche Y. Identification of a second promoter which drives the expression of gamma-glutamyl transpeptidase in rat kidney and epididymis. Biochemistry. 1992 Sep 29;31(38):9190–9196. doi: 10.1021/bi00153a011. [DOI] [PubMed] [Google Scholar]
  26. Lai E., Prezioso V. R., Tao W. F., Chen W. S., Darnell J. E., Jr Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes Dev. 1991 Mar;5(3):416–427. doi: 10.1101/gad.5.3.416. [DOI] [PubMed] [Google Scholar]
  27. Laperche Y., Bulle F., Aissani T., Chobert M. N., Aggerbeck M., Hanoune J., Guellaën G. Molecular cloning and nucleotide sequence of rat kidney gamma-glutamyl transpeptidase cDNA. Proc Natl Acad Sci U S A. 1986 Feb;83(4):937–941. doi: 10.1073/pnas.83.4.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mahendroo M. S., Mendelson C. R., Simpson E. R. Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem. 1993 Sep 15;268(26):19463–19470. [PubMed] [Google Scholar]
  29. Marceau N., Blouin M. J., Germain L., Noel M. Role of different epithelial cell types in liver ontogenesis, regeneration and neoplasia. In Vitro Cell Dev Biol. 1989 Apr;25(4):336–341. doi: 10.1007/BF02624596. [DOI] [PubMed] [Google Scholar]
  30. Mitchell P. J., Wang C., Tjian R. Positive and negative regulation of transcription in vitro: enhancer-binding protein AP-2 is inhibited by SV40 T antigen. Cell. 1987 Sep 11;50(6):847–861. doi: 10.1016/0092-8674(87)90512-5. [DOI] [PubMed] [Google Scholar]
  31. Pitot H. C. Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu Rev Pharmacol Toxicol. 1990;30:465–500. doi: 10.1146/annurev.pa.30.040190.002341. [DOI] [PubMed] [Google Scholar]
  32. Rajagopalan S., Park J. H., Patel P. D., Lebovitz R. M., Lieberman M. W. Cloning and analysis of the rat gamma-glutamyltransferase gene. J Biol Chem. 1990 Jul 15;265(20):11721–11725. [PubMed] [Google Scholar]
  33. Richardson C. C. Bacteriophage T7: minimal requirements for the replication of a duplex DNA molecule. Cell. 1983 Jun;33(2):315–317. doi: 10.1016/0092-8674(83)90411-7. [DOI] [PubMed] [Google Scholar]
  34. Roux J., Pictet R., Grange T. Hepatocyte nuclear factor 3 determines the amplitude of the glucocorticoid response of the rat tyrosine aminotransferase gene. DNA Cell Biol. 1995 May;14(5):385–396. doi: 10.1089/dna.1995.14.385. [DOI] [PubMed] [Google Scholar]
  35. Ruan H., Hill J. R., Fatemie-Nainie S., Morris D. R. Cell-specific translational regulation of S-adenosylmethionine decarboxylase mRNA. Influence of the structure of the 5' transcript leader on regulation by the upstream open reading frame. J Biol Chem. 1994 Jul 8;269(27):17905–17910. [PubMed] [Google Scholar]
  36. Sawaya P. L., Stripp B. R., Whitsett J. A., Luse D. S. The lung-specific CC10 gene is regulated by transcription factors from the AP-1, octamer, and hepatocyte nuclear factor 3 families. Mol Cell Biol. 1993 Jul;13(7):3860–3871. doi: 10.1128/mcb.13.7.3860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sell S., Dunsford H. A. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol. 1989 Jun;134(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  38. Sigal S. H., Brill S., Fiorino A. S., Reid L. M. The liver as a stem cell and lineage system. Am J Physiol. 1992 Aug;263(2 Pt 1):G139–G148. doi: 10.1152/ajpgi.1992.263.2.G139. [DOI] [PubMed] [Google Scholar]
  39. Suzuki T., Okuno H., Yoshida T., Endo T., Nishina H., Iba H. Difference in transcriptional regulatory function between c-Fos and Fra-2. Nucleic Acids Res. 1991 Oct 25;19(20):5537–5542. doi: 10.1093/nar/19.20.5537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thompson E. B., Tomkins G. M., Curran J. F. Induction of tyrosine alpha-ketoglutarate transaminase by steroid hormones in a newly established tissue culture cell line. Proc Natl Acad Sci U S A. 1966 Jul;56(1):296–303. doi: 10.1073/pnas.56.1.296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Van Eyken P., Sciot R., Paterson A., Callea F., Kew M. C., Desmet V. J. Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. Hum Pathol. 1988 May;19(5):562–568. doi: 10.1016/s0046-8177(88)80205-3. [DOI] [PubMed] [Google Scholar]
  42. van Dijk M. A., Rodenburg R. J., Holthuizen P., Sussenbach J. S. The liver-specific promoter of the human insulin-like growth factor II gene is activated by CCAAT/enhancer binding protein (C/EBP). Nucleic Acids Res. 1992 Jun 25;20(12):3099–3104. doi: 10.1093/nar/20.12.3099. [DOI] [PMC free article] [PubMed] [Google Scholar]

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