Biopolym. Cell. 2002; 18(2):142-154.
A role of upstrteam stimulatory factor-2a in regulation of plasminogen activator inhibitor-1 expression
- Institute of Biochemistry and Molecular Cell Biology
Humboldtallee 23, D-37073 Gettingen, Germany
- Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
The plasminogen activator inhibitor-1 (PAI-1) expression is induced by mild hypoxia (8 % O2) via the PAI-1 promoter region -175/-159 containing a hypoxia response element (HRE-2) binding the hypoxia inducible factor-1 (HIF-1) and an adjacent response element (HRE-1) binding a so far unknown factor. The aim of the present study was to identify this factor and to investigate its role in the regulation of PAI-1 expression. It was found by supershift assays that the upstream stimulatory factor-2a (USF-2a) is bound mainly to HRE-1 of the PAI-1 promoter and to a lesser extent to HRE-2. The USF-2a overexpression inhibited both PAI-1 mRNA and protein expression in primary cultured rat hepatocytes under normoxia and hypoxia. The Luciferase (Luc) reporter gene constructions driven by 766 and 276 bp of the 5'-flanking region of the rat PAI-1 gene were transiently transfected into primary rat hepatocytes together with the expression vectors encoding a wild type USF-2a and a USF-2a mutant lacking DNA-binding and dimerization activity (ΔHU2a). The cotransfection of the wild type USF-2a vector reduced the Luc activity by about 8 fold, whereas the cotransfection of ΔHU2a did not influence this activity. Mutation of the HRE-1 (-175/-168) in the rat PAI-1 promoter Luc constractions decreased the VSF-dependent inhibition of the Luc activity. Mutation of the HRE-2 (-165/-158) was less effective. These results indicated that the balance between two transcriptional factors, HIF-I and USF-2a, which could bind adjacent the HRE sites, appeared to be involved in the regulation of the PAI-1 expression under many clinical conditions.
 Lijnen HR, Collen D. Mechanisms of plasminogen activation by mammalian plasminogen activators. Enzyme. 1988;40(2-3):90-6.
 Kruithof EK, Vassalli JD, Schleuning WD, Mattaliano RJ, Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem. 1986;261(24):11207-13.
 Fearns C, Loskutoff DJ. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha. Am J Pathol. 1997;150(2):579-90.
 van Mourik JA, Lawrence DA, Loskutoff DJ. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem. 1984;259(23):14914-21.
 Erickson LA, Hekman CM, Loskutoff DJ. The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related. Proc Natl Acad Sci U S A. 1985;82(24):8710-4.
 Reilly CF, McFall RC. Platelet-derived growth factor and transforming growth factor-beta regulate plasminogen activator inhibitor-1 synthesis in vascular smooth muscle cells. J Biol Chem. 1991;266(15):9419-27.
 Busso N, Nicodeme E, Chesne C, Guillouzo A, Belin D, Hyafil F. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents. Hepatology. 1994;20(1 Pt 1):186-90.
 Le Magueresse-Battistoni B, Pernod G, Kolodi? L, Morera AM, Benahmed M. Tumor necrosis factor-alpha regulates plasminogen activator inhibitor-1 in rat testicular peritubular cells. Endocrinology. 1997;138(3):1097-105.
 Heaton JH, Nebes VL, O'Dell LG, Morris SM Jr, Gelehrter TD. Glucocorticoid and cyclic nucleotide regulation of plasminogen activator and plasminogen activator-inhibitor gene expression in primary cultures of rat hepatocytes. Mol Endocrinol. 1989;3(1):185-92.
 Podor TJ, Loskutoff DJ. Immunoelectron microscopic localization of type 1 plasminogen activator inhibitor in the extracellular matrix of transforming growth factor-beta-activated endothelial cells. Ann N Y Acad Sci. 1992;667:46-9.
 Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol. 1990;68(1):1-19. Review.
 Carmeliet P, Stassen JM, Schoonjans L, Ream B, van den Oord JJ, De Mol M, Mulligan RC, Collen D. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993;92(6):2756-60.
 Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, Simon RH. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest. 1996;97(1):232-7.
 Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood. 1999;94(12):4177-85.
 Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270(3):1230-7.
 Sawadogo M, Roeder RG. Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell. 1985;43(1):165-75.
 Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989;56(5):777-83.
 Pognonec P, Roeder RG. Recombinant 43-kDa USF binds to DNA and activates transcription in a manner indistinguishable from that of natural 43/44-kDa USF. Mol Cell Biol. 1991;11(10):5125-36.
 Sirito M, Lin Q, Maity T, Sawadogo M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res. 1994;22(3):427-33.
 Viollet B, Lefran?ois-Martinez AM, Henrion A, Kahn A, Raymondjean M, Martinez A. Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J Biol Chem. 1996;271(3):1405-15.
 Bruzdzinski CJ, Riordan-Johnson M, Nordby EC, Suter SM, Gelehrter TD. Isolation and characterization of the rat plasminogen activator inhibitor-1 gene. J Biol Chem. 1990;265(4):2078-85.
 Bruzdzinski CJ, Johnson MR, Goble CA, Winograd SS, Gelehrter TD. Mechanism of glucocorticoid induction of the rat plasminogen activator inhibitor-1 gene in HTC rat hepatoma cells: identification of cis-acting regulatory elements. Mol Endocrinol. 1993;7(9):1169-77.
 Lefran?ois-Martinez AM, Martinez A, Antoine B, Raymondjean M, Kahn A. Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J Biol Chem. 1995;270(6):2640-3.
 Kietzmann T, Roth U, Freimann S, Jungermann K. Arterial oxygen partial pressures reduce the insulin-dependent induction of the perivenously located glucokinase in rat hepatocyte cultures: mimicry of arterial oxygen pressures by H2O2. Biochem J. 1997;321 ( Pt 1):17-20.
 Zeheb R, Rafferty UM, Rodriguez MA, Andreasen P, Gelehrter TD. Immunoaffinity purification of HTC rat hepatoma cell plasminogen activator-inhibitor-1. Thromb Haemost. 1987;58(4):1017-23.
 Immenschuh S, Hinke V, Ohlmann A, Gifhorn-Katz S, Katz N, Jungermann K, Kietzmann T. Transcriptional activation of the haem oxygenase-1 gene by cGMP via a cAMP response element/activator protein-1 element in primary cultures of rat hepatocytes. Biochem J. 1998;334 ( Pt 1):141-6.
 Immenschuh S, Nagae Y, Satoh H, Baumann H, Muller-Eberhard U. The rat and human hemopexin genes contain an identical interleukin-6 response element that is not a target of CAAT enhancer-binding protein isoforms. J Biol Chem. 1994;269(17):12654-61.
 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;11(5):1475-89.
 Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447-54.
 Johnson MR, Bruzdzinski CJ, Winograd SS, Gelehrter TD. Regulatory sequences and protein-binding sites involved in the expression of the rat plasminogen activator inhibitor-1 gene. J Biol Chem. 1992;267(17):12202-10.
 Boyd KE, Farnham PJ. Myc versus USF: discrimination at the cad gene is determined by core promoter elements. Mol Cell Biol. 1997;17(5):2529-37.
 Boyd KE, Farnham PJ. Coexamination of site-specific transcription factor binding and promoter activity in living cells. Mol Cell Biol. 1999;19(12):8393-9.
 Carter RS, Ordentlich P, Kadesch T. Selective utilization of basic helix-loop-helix-leucine zipper proteins at the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1997;17(1):18-23.
 Takahashi Y, Nakayama K, Itoh S, Fujii-Kuriyama Y, Kamataki T. Inhibition of the transcription of CYP1A1 gene by the upstream stimulatory factor 1 in rabbits. Competitive binding of USF1 with AhR.Arnt complex. J Biol Chem. 1997;272(48):30025-31.
 Lun Y, Sawadogo M, Perry M. Autoactivation of Xenopus MyoD transcription and its inhibition by USF. Cell Growth Differ. 1997;8(3):275-82.
 Reisman D, Rotter V. The helix-loop-helix containing transcription factor USF binds to and transactivates the promoter of the p53 tumor suppressor gene. Nucleic Acids Res. 1993;21(2):345-50.
 Cogswell JP, Godlevski MM, Bonham M, Bisi J, Babiss L. Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 gene promoter. Mol Cell Biol. 1995;15(5):2782-90.
 Scholtz B, Kingsley-Kallesen M, Rizzino A. Transcription of the transforming growth factor-beta2 gene is dependent on an E-box located between an essential cAMP response element/activating transcription factor motif and the TATA box of the gene. J Biol Chem. 1996;271(50):32375-80.
 Wang D, Sul HS. Upstream stimulatory factors bind to insulin response sequence of the fatty acid synthase promoter. USF1 is regulated. J Biol Chem. 1995;270(48):28716-22.
 Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean M, Kahn A, Vaulont S. Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J Biol Chem. 1998;273(32):20175-9.
 White LA, Bruzdzinski C, Kutz SM, Gelehrter TD, Higgins PJ. Growth state-dependent binding of USF-1 to a proximal promoter E box element in the rat plasminogen activator inhibitor type 1 gene. Exp Cell Res. 2000;260(1):127-35.
 Bendall AJ, Molloy PL. Base preferences for DNA binding by the bHLH-Zip protein USF: effects of MgCl2 on specificity and comparison with binding of Myc family members. Nucleic Acids Res. 1994;22(14):2801-10.
 Chodosh LA, Carthew RW, Morgan JG, Crabtree GR, Sharp PA. The adenovirus major late transcription factor activates the rat gamma-fibrinogen promoter. Science. 1987;238(4827):684-8.
 Carthew RW, Chodosh LA, Sharp PA. The major late transcription factor binds to and activates the mouse metallothionein I promoter. Genes Dev. 1987;1(9):973-80.
 Ribeiro A, Pastier D, Kardassis D, Chambaz J, Cardot P. Cooperative binding of upstream stimulatory factor and hepatic nuclear factor 4 drives the transcription of the human apolipoprotein A-II gene. J Biol Chem. 1999;274(3):1216-25.
 Ghosh AK, Datta PK, Jacob ST. The dual role of helix-loop--helix-zipper protein USF in ribosomal RNA gene transcription in vivo. Oncogene. 1997;14(5):589-94.
 Aperlo C, Boulukos KE, Pognonec P. The basic region/helix-loop-helix/leucine repeat transcription factor USF interferes with Ras transformation. Eur J Biochem. 1996;241(1):249-53.
 Huang LE, Arany Z, Livingston DM, Bunn HF. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996;271(50):32253-9.
 Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J. 1998;17(22):6573-86.
 Luo X, Sawadogo M. Antiproliferative properties of the USF family of helix-loop-helix transcription factors. Proc Natl Acad Sci U S A. 1996;93(3):1308-13.
 Qyang Y, Luo X, Lu T, Ismail PM, Krylov D, Vinson C, Sawadogo M. Cell-type-dependent activity of the ubiquitous transcription factor USF in cellular proliferation and transcriptional activation. Mol Cell Biol. 1999;19(2):1508-17.
 Ismail PM, Lu T, Sawadogo M. Loss of USF transcriptional activity in breast cancer cell lines. Oncogene. 1999;18(40):5582-91.
 Reilly D, Andreseasen P, Duffy MJ. Studies on plasminogen activator inhibitor 1 levels in human breast cancer. Biochem Soc Trans. 1990;18(2):354-5.
 Liu G, Shuman MA, Cohen RL. Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int J Cancer. 1995;60(4):501-6.
 Pedersen H, Br?nner N, Francis D, Osterlind K, R?nne E, Hansen HH, Dan? K, Gr?ndahl-Hansen J. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 1994;54(17):4671-5.
 Gr?ndahl-Hansen J, Christensen IJ, Rosenquist C, Br?nner N, Mouridsen HT, Dan? K, Blichert-Toft M. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 1993;53(11):2513-21.
 Kuhn W, Pache L, Schmalfeldt B, Dettmar P, Schmitt M, J?nicke F, Graeff H. Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol Oncol. 1994;55(3 Pt 1):401-9.