Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1995 Feb 11;23(3):395–404. doi: 10.1093/nar/23.3.395

Hierarchy and positive/negative interplays of the hepatocyte nuclear factors HNF-1, -3 and -4 in the liver-specific enhancer for the human alpha-1-microglobulin/bikunin precursor.

P Rouet 1, G Raguenez 1, F Tronche 1, V Mfou'ou 1, J P Salier 1
PMCID: PMC306689  PMID: 7533900

Abstract

Alpha-1-microglobulin and bikunin are two plasma glycoproteins encoded by an alpha-1-microglobulin/bikunin precursor (AMBP) gene. The strict liver-specific expression of the AMBP gene is controlled by a potent enhancer made of six clustered boxes numbered 1-6 that have been reported to be proven or potential binding sites for the hepatocyte-enriched nuclear factors HNF-1, -4, -3, -1, -3, -4, respectively. In the present study, electromobility shift assays of wild-type or mutated probes demonstrated that the boxes 1-5 have a binding capacity for their cognate HNF protein. Box 5 is also a target for another, as yet unidentified, factor. A functional analysis of the wild-type or mutated enhancer, driving its homologous promoter and a reporter CAT gene in the HepG2 hepatoma cell line, demonstrated that all six boxes participate in the enhancer activity, with the primary influence of box 4 (HNF-1) and box 2 (HNF-4). A similar analysis in the HNF-free CHO cell line co-transfected with one or several HNF factors further demonstrated various interplays between boxes: box 3 (HNF-3 alpha and beta) has a negative influence over the major HNF-4 box 2 as well as a positive influence over the major HNF-1 box 4.

Full text

PDF
397

Images in this article

398Image
on p.398
399Image
on p.399
400Image
on p.400

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akerström B., Lögdberg L. An intriguing member of the lipocalin protein family: alpha 1-microglobulin. Trends Biochem Sci. 1990 Jun;15(6):240–243. doi: 10.1016/0968-0004(90)90037-c. [DOI] [PubMed] [Google Scholar]
  2. Bach I., Yaniv M. More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. EMBO J. 1993 Nov;12(11):4229–4242. doi: 10.1002/j.1460-2075.1993.tb06107.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boshart M., Klüppel M., Schmidt A., Schütz G., Luckow B. Reporter constructs with low background activity utilizing the cat gene. Gene. 1992 Jan 2;110(1):129–130. doi: 10.1016/0378-1119(92)90456-y. [DOI] [PubMed] [Google Scholar]
  4. Cereghini S., Blumenfeld M., Yaniv M. A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells. Genes Dev. 1988 Aug;2(8):957–974. doi: 10.1101/gad.2.8.957. [DOI] [PubMed] [Google Scholar]
  5. Chen L., Mao S. J., Larsen W. J. Identification of a factor in fetal bovine serum that stabilizes the cumulus extracellular matrix. A role for a member of the inter-alpha-trypsin inhibitor family. J Biol Chem. 1992 Jun 15;267(17):12380–12386. [PubMed] [Google Scholar]
  6. Daveau M., Rouet P., Scotte M., Faye L., Hiron M., Lebreton J. P., Salier J. P. Human inter-alpha-inhibitor family in inflammation: simultaneous synthesis of positive and negative acute-phase proteins. Biochem J. 1993 Jun 1;292(Pt 2):485–492. doi: 10.1042/bj2920485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Diarra-Mehrpour M., Bourguignon J., Sesboü R., Salier J. P., Léveillard T., Martin J. P. Structural analysis of the human inter-alpha-trypsin inhibitor light-chain gene. Eur J Biochem. 1990 Jul 20;191(1):131–139. doi: 10.1111/j.1432-1033.1990.tb19102.x. [DOI] [PubMed] [Google Scholar]
  8. Escribano J., Grubb A., Méndez E. Identification of retinol as one of the protein HC chromophores. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1424–1429. doi: 10.1016/s0006-291x(88)81300-7. [DOI] [PubMed] [Google Scholar]
  9. Godovac-Zimmermann J. The structural motif of beta-lactoglobulin and retinol-binding protein: a basic framework for binding and transport of small hydrophobic molecules? Trends Biochem Sci. 1988 Feb;13(2):64–66. doi: 10.1016/0968-0004(88)90031-x. [DOI] [PubMed] [Google Scholar]
  10. Gregori C., Kahn A., Pichard A. L. Activity of the rat liver-specific aldolase B promoter is restrained by HNF3. Nucleic Acids Res. 1994 Apr 11;22(7):1242–1246. doi: 10.1093/nar/22.7.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ham J., Dostatni N., Arnos F., Yaniv M. Several different upstream promoter elements can potentiate transactivation by the BPV-1 E2 protein. EMBO J. 1991 Oct;10(10):2931–2940. doi: 10.1002/j.1460-2075.1991.tb07843.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Kaumeyer J. F., Polazzi J. O., Kotick M. P. The mRNA for a proteinase inhibitor related to the HI-30 domain of inter-alpha-trypsin inhibitor also encodes alpha-1-microglobulin (protein HC). Nucleic Acids Res. 1986 Oct 24;14(20):7839–7850. doi: 10.1093/nar/14.20.7839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kimura A., Nishiyori A., Murakami T., Tsukamoto T., Hata S., Osumi T., Okamura R., Mori M., Takiguchi M. Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) represses transcription from the promoter of the gene for ornithine transcarbamylase in a manner antagonistic to hepatocyte nuclear factor-4 (HNF-4). J Biol Chem. 1993 May 25;268(15):11125–11133. [PubMed] [Google Scholar]
  15. Lai E., Clark K. L., Burley S. K., Darnell J. E., Jr Hepatocyte nuclear factor 3/fork head or "winged helix" proteins: a family of transcription factors of diverse biologic function. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10421–10423. doi: 10.1073/pnas.90.22.10421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lindqvist A., Bratt T., Altieri M., Kastern W., Akerström B. Rat alpha 1-microglobulin: co-expression in liver with the light chain of inter-alpha-trypsin inhibitor. Biochim Biophys Acta. 1992 Feb 28;1130(1):63–67. doi: 10.1016/0167-4781(92)90462-9. [DOI] [PubMed] [Google Scholar]
  17. McKeehan W. L., Sakagami Y., Hoshi H., McKeehan K. A. Two apparent human endothelial cell growth factors from human hepatoma cells are tumor-associated proteinase inhibitors. J Biol Chem. 1986 Apr 25;261(12):5378–5383. [PubMed] [Google Scholar]
  18. McPherson C. E., Shim E. Y., Friedman D. S., Zaret K. S. An active tissue-specific enhancer and bound transcription factors existing in a precisely positioned nucleosomal array. Cell. 1993 Oct 22;75(2):387–398. doi: 10.1016/0092-8674(93)80079-t. [DOI] [PubMed] [Google Scholar]
  19. Mendel D. B., Crabtree G. R. HNF-1, a member of a novel class of dimerizing homeodomain proteins. J Biol Chem. 1991 Jan 15;266(2):677–680. [PubMed] [Google Scholar]
  20. Metzger S., Halaas J. L., Breslow J. L., Sladek F. M. Orphan receptor HNF-4 and bZip protein C/EBP alpha bind to overlapping regions of the apolipoprotein B gene promoter and synergistically activate transcription. J Biol Chem. 1993 Aug 5;268(22):16831–16838. [PubMed] [Google Scholar]
  21. Miura N., Tanaka K. Analysis of the rat hepatocyte nuclear factor (HNF) 1 gene promoter: synergistic activation by HNF4 and HNF1 proteins. Nucleic Acids Res. 1993 Aug 11;21(16):3731–3736. doi: 10.1093/nar/21.16.3731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nishiyori A., Tashiro H., Kimura A., Akagi K., Yamamura K., Mori M., Takiguchi M. Determination of tissue specificity of the enhancer by combinatorial operation of tissue-enriched transcription factors. Both HNF-4 and C/EBP beta are required for liver-specific activity of the ornithine transcarbamylase enhancer. J Biol Chem. 1994 Jan 14;269(2):1323–1331. [PubMed] [Google Scholar]
  23. Perrin S., Gilliland G. Site-specific mutagenesis using asymmetric polymerase chain reaction and a single mutant primer. Nucleic Acids Res. 1990 Dec 25;18(24):7433–7438. doi: 10.1093/nar/18.24.7433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Raymondjean M., Pichard A. L., Gregori C., Ginot F., Kahn A. Interplay of an original combination of factors: C/EBP, NFY, HNF3, and HNF1 in the rat aldolase B gene promoter. Nucleic Acids Res. 1991 Nov 25;19(22):6145–6153. doi: 10.1093/nar/19.22.6145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rouet P., Raguenez G., Salier J. P. Optimized assays for quantifying transient expressions of co-transfected beta-galactosidase and CAT reporter genes. Biotechniques. 1992 Nov;13(5):700–701. [PubMed] [Google Scholar]
  26. Rouet P., Raguenez G., Tronche F., Yaniv M., N'Guyen C., Salier J. P. A potent enhancer made of clustered liver-specific elements in the transcription control sequences of human alpha 1-microglobulin/bikunin gene. J Biol Chem. 1992 Oct 15;267(29):20765–20773. [PubMed] [Google Scholar]
  27. Salier J. P., Chan P., Raguenez G., Zwingman T., Erickson R. P. Developmentally regulated transcription of the four liver-specific genes for inter-alpha-inhibitor family in mouse. Biochem J. 1993 Nov 15;296(Pt 1):85–91. doi: 10.1042/bj2960085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Salier J. P., Diarra-Mehrpour M., Sesboue R., Bourguignon J., Benarous R., Ohkubo I., Kurachi S., Kurachi K., Martin J. P. Isolation and characterization of cDNAs encoding the heavy chain of human inter-alpha-trypsin inhibitor (I alpha TI): unambiguous evidence for multipolypeptide chain structure of I alpha TI. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8272–8276. doi: 10.1073/pnas.84.23.8272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Salier J. P. Inter-alpha-trypsin inhibitor: emergence of a family within the Kunitz-type protease inhibitor superfamily. Trends Biochem Sci. 1990 Nov;15(11):435–439. doi: 10.1016/0968-0004(90)90282-g. [DOI] [PubMed] [Google Scholar]
  30. Wu K. J., Wilson D. R., Shih C., Darlington G. J. The transcription factor HNF1 acts with C/EBP alpha to synergistically activate the human albumin promoter through a novel domain. J Biol Chem. 1994 Jan 14;269(2):1177–1182. [PubMed] [Google Scholar]
  31. Xanthopoulos K. G., Mirkovitch J. Gene regulation in rodent hepatocytes during development, differentiation and disease. Eur J Biochem. 1993 Sep 1;216(2):353–360. doi: 10.1111/j.1432-1033.1993.tb18152.x. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES