Abstract
The human gene for plasminogen activator inhibitor type-1 (PAI-1) has been isolated and its promoter region characterized. PAI-1 regulation by glucocorticoids, transforming growth factor-beta (TGF-beta) and the phorbol ester PMA is shown to be exerted at the promoter level. A fragment spanning 805 nucleotides of the 5' flanking and 72 of the 5' untranslated region contain information enough to promote transcription and to respond to glucocorticoids when fused to a reporter gene and transfected into human fibrosarcoma cells. A moderately repetitive DNA sequence, containing a TATA box, a GRE consensus, a Z-DNA forming sequence and two imperfect direct repeats at the extremities, is present a few nucleotides 5' of the human PAI-1 gene transcription start site, raising the possibility that this gene could have been activated by DNA insertion during evolution.
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Selected References
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- Addison W. R., Kurtz D. T. Nucleotide sequences required for the regulation of a rat alpha 2u-globulin gene by glucocorticoids. Mol Cell Biol. 1986 Jul;6(7):2334–2346. doi: 10.1128/mcb.6.7.2334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andreasen P. A., Christensen T. H., Huang J. Y., Nielsen L. S., Wilson E. L., Danø K. Hormonal regulation of extracellular plasminogen activators and Mr approximately 54,000 plasminogen activator inhibitor in human neoplastic cell lines, studied with monoclonal antibodies. Mol Cell Endocrinol. 1986 May;45(2-3):137–147. doi: 10.1016/0303-7207(86)90141-3. [DOI] [PubMed] [Google Scholar]
- Andreasen P. A., Pyke C., Riccio A., Kristensen P., Nielsen L. S., Lund L. R., Blasi F., Danø K. Plasminogen activator inhibitor type 1 biosynthesis and mRNA level are increased by dexamethasone in human fibrosarcoma cells. Mol Cell Biol. 1987 Aug;7(8):3021–3025. doi: 10.1128/mcb.7.8.3021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andreasen P. A., Riccio A., Welinder K. G., Douglas R., Sartorio R., Nielsen L. S., Oppenheimer C., Blasi F., Danø K. Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett. 1986 Dec 15;209(2):213–218. doi: 10.1016/0014-5793(86)81113-9. [DOI] [PubMed] [Google Scholar]
- Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
- Bevilacqua M. P., Schleef R. R., Gimbrone M. A., Jr, Loskutoff D. J. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J Clin Invest. 1986 Aug;78(2):587–591. doi: 10.1172/JCI112613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blasi F., Vassalli J. D., Danø K. Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors. J Cell Biol. 1987 Apr;104(4):801–804. doi: 10.1083/jcb.104.4.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bonsall R. W., Hunt S. Characteristics of interactions between surfactants and the human erythrocyte membrane. Biochim Biophys Acta. 1971 Oct 12;249(1):266–280. doi: 10.1016/0005-2736(71)90104-0. [DOI] [PubMed] [Google Scholar]
- Busso N., Belin D., Failly-Crépin C., Vassalli J. D. Glucocorticoid modulation of plasminogen activators and of one of their inhibitors in the human mammary carcinoma cell line MDA-MB-231. Cancer Res. 1987 Jan 15;47(2):364–370. [PubMed] [Google Scholar]
- Castagna M., Takai Y., Kaibuchi K., Sano K., Kikkawa U., Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847–7851. [PubMed] [Google Scholar]
- Colantuoni V., Pirozzi A., Blance C., Cortese R. Negative control of liver-specific gene expression: cloned human retinol-binding protein gene is repressed in HeLa cells. EMBO J. 1987 Mar;6(3):631–636. doi: 10.1002/j.1460-2075.1987.tb04801.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coleman P. L., Patel P. D., Cwikel B. J., Rafferty U. M., Sznycer-Laszuk R., Gelehrter T. D. Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem. 1986 Mar 25;261(9):4352–4357. [PubMed] [Google Scholar]
- Comb M., Birnberg N. C., Seasholtz A., Herbert E., Goodman H. M. A cyclic AMP- and phorbol ester-inducible DNA element. 1986 Sep 25-Oct 1Nature. 323(6086):353–356. doi: 10.1038/323353a0. [DOI] [PubMed] [Google Scholar]
- Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
- Dente L., Cesareni G., Cortese R. pEMBL: a new family of single stranded plasmids. Nucleic Acids Res. 1983 Mar 25;11(6):1645–1655. doi: 10.1093/nar/11.6.1645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Diamond L., O'Brien T. G., Rovera G. Tumor promoters: effects on proliferation and differentiation of cells in culture. Life Sci. 1978 Nov 13;23(20):1979–1988. doi: 10.1016/0024-3205(78)90229-1. [DOI] [PubMed] [Google Scholar]
- Frischauf A. M., Lehrach H., Poustka A., Murray N. Lambda replacement vectors carrying polylinker sequences. J Mol Biol. 1983 Nov 15;170(4):827–842. doi: 10.1016/s0022-2836(83)80190-9. [DOI] [PubMed] [Google Scholar]
- Frolik C. A., Wakefield L. M., Smith D. M., Sporn M. B. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. J Biol Chem. 1984 Sep 10;259(17):10995–11000. [PubMed] [Google Scholar]
- Gelehrter T. D., Barouski-Miller P. A., Coleman P. L., Cwikel B. J. Hormonal regulation of plasminogen activator in rat hepatoma cells. Mol Cell Biochem. 1983;53-54(1-2):11–21. doi: 10.1007/BF00225243. [DOI] [PubMed] [Google Scholar]
- Ginsburg D., Zeheb R., Yang A. Y., Rafferty U. M., Andreasen P. A., Nielsen L., Dano K., Lebo R. V., Gelehrter T. D. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest. 1986 Dec;78(6):1673–1680. doi: 10.1172/JCI112761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grames M., Breviario F., Pintucci G., Millet I., Dejana E., van Damme J., Donati M. B., Mussoni L. Enhancement by interleukin-1 (IL-1) of plasminogen activator inhibitor (PA-I) activity in cultured human endothelial cells. Biochem Biophys Res Commun. 1986 Sep 14;139(2):720–727. doi: 10.1016/s0006-291x(86)80050-x. [DOI] [PubMed] [Google Scholar]
- Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
- Hamada H., Petrino M. G., Kakunaga T. A novel repeated element with Z-DNA-forming potential is widely found in evolutionarily diverse eukaryotic genomes. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6465–6469. doi: 10.1073/pnas.79.21.6465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanss M., Collen D. Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: modulation by thrombin, endotoxin, and histamine. J Lab Clin Med. 1987 Jan;109(1):97–104. [PubMed] [Google Scholar]
- Hattori M., Hidaka S., Sakaki Y. Sequence analysis of a KpnI family member near the 3' end of human beta-globin gene. Nucleic Acids Res. 1985 Nov 11;13(21):7813–7827. doi: 10.1093/nar/13.21.7813. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
- Jones K. A., Kadonaga J. T., Rosenfeld P. J., Kelly T. J., Tjian R. A cellular DNA-binding protein that activates eukaryotic transcription and DNA replication. Cell. 1987 Jan 16;48(1):79–89. doi: 10.1016/0092-8674(87)90358-8. [DOI] [PubMed] [Google Scholar]
- Kariya Y., Kato K., Hayashizaki Y., Himeno S., Tarui S., Matsubara K. Revision of consensus sequence of human Alu repeats--a review. Gene. 1987;53(1):1–10. doi: 10.1016/0378-1119(87)90087-4. [DOI] [PubMed] [Google Scholar]
- Kruithof E. K., Vassalli J. D., Schleuning W. D., Mattaliano R. J., Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem. 1986 Aug 25;261(24):11207–11213. [PubMed] [Google Scholar]
- Laiho M., Saksela O., Andreasen P. A., Keski-Oja J. Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta. J Cell Biol. 1986 Dec;103(6 Pt 1):2403–2410. doi: 10.1083/jcb.103.6.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee W., Mitchell P., Tjian R. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell. 1987 Jun 19;49(6):741–752. doi: 10.1016/0092-8674(87)90612-x. [DOI] [PubMed] [Google Scholar]
- Leof E. B., Proper J. A., Goustin A. S., Shipley G. D., DiCorleto P. E., Moses H. L. Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: a proposed model for indirect mitogenesis involving autocrine activity. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2453–2457. doi: 10.1073/pnas.83.8.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loskutoff D. J., Linders M., Keijer J., Veerman H., van Heerikhuizen H., Pannekoek H. Structure of the human plasminogen activator inhibitor 1 gene: nonrandom distribution of introns. Biochemistry. 1987 Jun 30;26(13):3763–3768. doi: 10.1021/bi00387a004. [DOI] [PubMed] [Google Scholar]
- Lund L. R., Riccio A., Andreasen P. A., Nielsen L. S., Kristensen P., Laiho M., Saksela O., Blasi F., Danø K. Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. EMBO J. 1987 May;6(5):1281–1286. doi: 10.1002/j.1460-2075.1987.tb02365.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Massagué J. Subunit structure of a high-affinity receptor for type beta-transforming growth factor. Evidence for a disulfide-linked glycosylated receptor complex. J Biol Chem. 1985 Jun 10;260(11):7059–7066. [PubMed] [Google Scholar]
- Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nachman R. L., Hajjar K. A., Silverstein R. L., Dinarello C. A. Interleukin 1 induces endothelial cell synthesis of plasminogen activator inhibitor. J Exp Med. 1986 Jun 1;163(6):1595–1600. doi: 10.1084/jem.163.6.1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nagamine Y., Pearson D., Altus M. S., Reich E. cDNA and gene nucleotide sequence of porcine plasminogen activator. Nucleic Acids Res. 1984 Dec 21;12(24):9525–9541. doi: 10.1093/nar/12.24.9525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nielsen L. S., Andreasen P. A., Grøndahl-Hansen J., Huang J. Y., Kristensen P., Danø K. Monoclonal antibodies to human 54,000 molecular weight plasminogen activator inhibitor from fibrosarcoma cells--inhibitor neutralization and one-step affinity purification. Thromb Haemost. 1986 Apr 30;55(2):206–212. [PubMed] [Google Scholar]
- Ny T., Elgh F., Lund B. The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5355–5359. doi: 10.1073/pnas.81.17.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ny T., Sawdey M., Lawrence D., Millan J. L., Loskutoff D. J. Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6776–6780. doi: 10.1073/pnas.83.18.6776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Oliver N., Newby R. F., Furcht L. T., Bourgeois S. Regulation of fibronectin biosynthesis by glucocorticoids in human fibrosarcoma cells and normal fibroblasts. Cell. 1983 May;33(1):287–296. doi: 10.1016/0092-8674(83)90357-4. [DOI] [PubMed] [Google Scholar]
- Paek I., Axel R. Glucocorticoids enhance stability of human growth hormone mRNA. Mol Cell Biol. 1987 Apr;7(4):1496–1507. doi: 10.1128/mcb.7.4.1496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pannekoek H., Veerman H., Lambers H., Diergaarde P., Verweij C. L., van Zonneveld A. J., van Mourik J. A. Endothelial plasminogen activator inhibitor (PAI): a new member of the Serpin gene family. EMBO J. 1986 Oct;5(10):2539–2544. doi: 10.1002/j.1460-2075.1986.tb04532.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parnes J. R., Seidman J. G. Structure of wild-type and mutant mouse beta 2-microglobulin genes. Cell. 1982 Jun;29(2):661–669. doi: 10.1016/0092-8674(82)90182-9. [DOI] [PubMed] [Google Scholar]
- Ponte P., Gunning P., Blau H., Kedes L. Human actin genes are single copy for alpha-skeletal and alpha-cardiac actin but multicopy for beta- and gamma-cytoskeletal genes: 3' untranslated regions are isotype specific but are conserved in evolution. Mol Cell Biol. 1983 Oct;3(10):1783–1791. doi: 10.1128/mcb.3.10.1783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Riccio A., Grimaldi G., Verde P., Sebastio G., Boast S., Blasi F. The human urokinase-plasminogen activator gene and its promoter. Nucleic Acids Res. 1985 Apr 25;13(8):2759–2771. doi: 10.1093/nar/13.8.2759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rich A., Nordheim A., Wang A. H. The chemistry and biology of left-handed Z-DNA. Annu Rev Biochem. 1984;53:791–846. doi: 10.1146/annurev.bi.53.070184.004043. [DOI] [PubMed] [Google Scholar]
- Saffer J. D., Lerman M. I. Unusual class of Alu sequences containing a potential Z-DNA segment. Mol Cell Biol. 1983 May;3(5):960–964. doi: 10.1128/mcb.3.5.960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sporn M. B., Roberts A. B., Wakefield L. M., de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. doi: 10.1083/jcb.105.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sprengers E. D., Kluft C. Plasminogen activator inhibitors. Blood. 1987 Feb;69(2):381–387. [PubMed] [Google Scholar]
- Sundström C., Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976 May 15;17(5):565–577. doi: 10.1002/ijc.2910170504. [DOI] [PubMed] [Google Scholar]
- Thalacker F. W., Nilsen-Hamilton M. Specific induction of secreted proteins by transforming growth factor-beta and 12-O-tetradecanoylphorbol-13-acetate. Relationship with an inhibitor of plasminogen activator. J Biol Chem. 1987 Feb 15;262(5):2283–2290. [PubMed] [Google Scholar]
- Tucker R. F., Branum E. L., Shipley G. D., Ryan R. J., Moses H. L. Specific binding to cultured cells of 125I-labeled type beta transforming growth factor from human platelets. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6757–6761. doi: 10.1073/pnas.81.21.6757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Hinsbergh V. W., Sprengers E. D., Kooistra T. Effect of thrombin on the production of plasminogen activators and PA inhibitor-1 by human foreskin microvascular endothelial cells. Thromb Haemost. 1987 Apr 7;57(2):148–153. [PubMed] [Google Scholar]
- Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., Axel R. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell. 1979 Apr;16(4):777–785. doi: 10.1016/0092-8674(79)90093-x. [DOI] [PubMed] [Google Scholar]
- Wun T. C., Kretzmer K. K. cDNA cloning and expression in E. coli of a plasminogen activator inhibitor (PAI) related to a PAI produced by Hep G2 hepatoma cell. FEBS Lett. 1987 Jan 1;210(1):11–16. doi: 10.1016/0014-5793(87)81288-7. [DOI] [PubMed] [Google Scholar]
- Yamamoto K. R. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. doi: 10.1146/annurev.ge.19.120185.001233. [DOI] [PubMed] [Google Scholar]
- Yanisch-Perron C., Vieira J., Messing J. Improved M13 phage cloning vectors and host strains: nucleotide sequences of the M13mp18 and pUC19 vectors. Gene. 1985;33(1):103–119. doi: 10.1016/0378-1119(85)90120-9. [DOI] [PubMed] [Google Scholar]
- Ye R. D., Wun T. C., Sadler J. E. cDNA cloning and expression in Escherichia coli of a plasminogen activator inhibitor from human placenta. J Biol Chem. 1987 Mar 15;262(8):3718–3725. [PubMed] [Google Scholar]