Transcriptional regulation of the plasminogen activator inhibitor type 1 – with an emphasis on negative regulation

Yoshikuni Nagamine

doi:10.1160/TH08-05-0294

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(06): 1007-1013
DOI: 10.1160/TH08-05-0294

Theme Issue Article

Schattauer GmbH

Transcriptional regulation of the plasminogen activator inhibitor type 1 – with an emphasis on negative regulation

Yoshikuni Nagamine

¹Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland

› Author Affiliations

Abstract

Summary

By inhibiting plasminogen activators uPA and tPA, inducing uPAuPAR internalization and interfering with the interaction between extracellular matrix protein vitronectin and αvβ3 integrin, plasminogen activator inhibitor type 1 (PAI-1) is active in the regulation of various biological processes involving extracellular proteolysis and tissue remodeling. PAI-1 is expressed in many cell types under the control of a variety of signals, depending on cell type. The most prominent and important of these signals are TGFβ, hypoxia and insulin. Although the signaling pathways were largely elucidated, recent investigations have revealed more complicated aspects. The pathways interact at the level of both transcription factors and regulatory elements on the promoter. Furthermore, the engagement of negative factors in these pathways has been shown to be important, adding complexity and versatility to PAI-1 gene regulation.

Keywords

Review - plasminogen activator - gene regulation - negative regulation

Full Text

References

References
1 Binder BR, Christ G, Gruber F. et al. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci 2002; 17: 56-61.
2 Durand MK, Bodker JS, Christensen A. et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004; 91: 438-449.
3 Seiffert D, Smith JW. The cell adhesion domain in plasma vitronectin is cryptic. J Biol Chem 1997; 272: 13705-13710.
4 Cubellis MV, Wun TC, Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 1990; 09: 1079-1085.
5 Degryse B, Sier CF, Resnati M. et al. PAI-1 inhibits urokinase-induced chemotaxis by internalizing the urokinase receptor. FEBS Lett 2001; 505: 249-254.
6 Lijnen HR. Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 2005; 03: 35-45.
7 Kretzschmar M, Massague J. SMADs: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 1998; 08: 103-111.
8 Westerhausen Jr DR, Hopkins WE, Billadello JJ. Multiple transforming growth factor-beta-inducible elements regulate expression of the plasminogen activator inhibitor type-1 gene in Hep G2 cells. J Biol Chem 1991; 266: 1092-1100.
9 Riccio A, Pedone PV, Lund LR. et al. Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene. Mol Cell Biol 1992; 12: 1846-1855.
10 Dennler S, Itoh S, Vivien D. et al. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J 1998; 17: 3091-3100.
11 Song CZ, Siok TE, Gelehrter TD. Smad4/DPC4 and Smad3 mediate transforming growth factor-beta (TGF-beta) signaling through direct binding to a novel TGF-beta-responsive element in the human plasminogen activator inhibitor-1 promoter. J Biol Chem 1998; 273: 29287-29290.
12 Hua X, Liu X, Ansari DO. et al. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Genes Dev 1998; 12: 3084-3095.
13 Feng XH, Zhang Y, Wu RY. et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev 1998; 12: 2153-2163.
14 Datta PK, Blake MC, Moses HL. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. J Biol Chem 2000; 275: 40014-40019.
15 Lu Z, Lam KS, Wang N. et al. LMO4 can interact with Smad proteins and modulate transforming growth factor-beta signaling in epithelial cells. Oncogene 2006; 25: 2920-2930.
16 Song CZ, Tian X, Gelehrter TD. Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Proc Natl Acad Sci USA 1999; 96: 11776-11781.
17 Li G, Heaton JH, Gelehrter TD. Role of steroid receptor coactivators in glucocorticoid and transforming growth factor beta regulation of plasminogen activator inhibitor gene expression. Mol Endocrinol 2006; 20: 1025-1034.
18 Boon RA, Fledderus JO, Volger OL. et al. KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1. Arterioscler Thromb Vasc Biol 2007; 27: 532-539.
19 Atkins GB, Jain MK. Role of Kruppel-like transcription factors in endothelial biology. Circ Res 2007; 100: 1686-1695.
20 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: 4177-4185.
21 Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93: 266-276.
22 Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337-1340.
23 Lando D, Peet DJ, Gorman JJ. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002; 16: 1466-1471.
24 Kvietikova I, Wenger RH, Marti HH. et al. The transcription factors ATF-1 and CREB-1 bind constitutively to the hypoxia-inducible factor-1 (HIF-1) DNA recognition site. Nucleic Acids Res 1995; 23: 4542-4550.
25 Gerber HP, Condorelli F, Park J. et al. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 1997; 272: 23659-23667.
26 Gertler JP, Perry L, L’Italien G. et al. Ambient oxygen tension modulates endothelial fibrinolysis. J Vasc Surg 1993; 18: 939-46.
27 Fink T, Kazlauskas A, Poellinger L. et al. Identification ofa tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood 2002; 99: 2077-2083.
28 Sato M, Tanaka T, Maemura K. et al. The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells. AmJ Respir Cell Mol Biol 2004; 31: 209-215.
29 Sato M, Tanaka T, Maeno T. et al. Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway. Am J Respir Cell Mol Biol 2002; 26: 127-134.
30 Zhang Q, Wu Y, Chau CH. et al. Crosstalk of hypoxia-mediated signaling pathways in upregulating plasminogen activator inhibitor-1 expression in keloid fibroblasts. J Cell Physiol 2004; 199: 89-97.
31 Chau CH, Clavijo CA, Deng HT. et al. Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems. Am J Physiol Cell Physiol 2005; 289: C444-454.
32 Kietzmann T, Samoylenko A, Roth U. et al. Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes. Blood 2003; 101: 907-914.
33 Dimova EY, Moller U, Herzig S. et al. Transcriptional regulation of plasminogen activator inhibitor-1 expression by insulin-like growth factor-1 via MAP kinases and hypoxia-inducible factor-1 in HepG2 cells. Thromb Haemost 2005; 93: 1176-1184.
34 Kvietikova I, Wenger RH, Marti HH. et al. The hypoxia-inducible factor-1 DNA recognition site is cAMP-responsive. Kidney Int 1997; 51: 564-566.
35 Dimova EY, Jakubowska MM, Kietzmann T. CREB binding to the hypoxia-inducible factor-1 responsive elements in the plasminogen activator inhibitor-1 promoter mediates the glucagon effect. Thromb Haemost 2007; 98: 296-303.
36 Samoylenko A, Roth U, Jungermann K. et al. The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site. Blood 2001; 97: 2657-2666.
37 Gross C, Buchwalter G, Dubois-Pot H. et al. The ternary complex factor net is downregulated by hypoxia and regulates hypoxia-responsive genes. Mol Cell Biol 2007; 27: 4133-4141.
38 Buchwalter G, Gross C, Wasylyk B. The ternary complex factor Net regulates cell migration through inhibition of PAI-1 expression. Mol Cell Biol 2005; 25: 10853-10862.
39 Samad F, Loskutoff DJ. The fat mouse: a powerful genetic model to study elevated plasminogen activator inhibitor1 in obesity/NIDDM. Thromb Haemost 1997; 78: 652-655.
40 Mavri A, Alessi MC, Bastelica D. et al. Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss. Diabetologia 2001; 44: 2025-2031.
41 Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004; 28: 1357-1364.
42 Alessi MC, Poggi M, Juhan-Vague I. Plasminogen activator inhibitor-1, adipose tissue and insulin resistance. Curr Opin Lipidol 2007; 18: 240-245.
43 Whitman M, Kaplan DR, Schaffhausen BS. et al. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985; 315: 239-242.
44 Johnston AM, Pirola L, Van Obberghen E. Molecular mechanisms of insulin receptor substrate proteinmediated modulation of insulin signalling. FEBS Lett 2003; 546: 32-36.
45 Youngren JF. Regulation of insulin receptor function. Cell Mol Life Sci 2007; 64: 873-891.
46 Saltiel AR, Pessin JE. Insulin signaling pathways in time and space. Trends Cell Biol 2002; 12: 65-71.
47 Samad F, Pandey M, Bell PA. et al. Insulin continues to induce plasminogen activator inhibitor1 gene expression in insulin-resistant mice and adipocytes. Mol Med 2000; 06: 680-692.
48 Griffiths MR, Black EJ, Culbert AA. et al. Insulinstimulated expression of c-fos, fra1 and c-jun accompanies the activation of the activator protein-1 (AP-1) transcriptional complex. Biochem J 1998; 335: 19-26.
49 Dimova EY, Kietzmann T. The MAPK pathway and HIF-1 are involved in the induction of the human PAI-1 gene expression by insulin in the human hepatoma cell line HepG2. AnnN Y Acad Sci 2006; 1090: 355-367.
50 Venugopal J, Hanashiro K, Nagamine Y. Regulation of PAI-1 gene expression during adipogenesis. J Cell Biochem 2007; 101: 369-380.
51 Mukai Y, Wang CY, Rikitake Y. et al. Phosphatidylinositol 3-kinase/protein kinase Akt negatively regulates plasminogen activator inhibitor type 1 expression in vascular endothelial cells. Am J Physiol Heart Circ Physiol 2007; 292: H1937-1942.
52 Venugopal J, Hanashiro K, Yang ZZ. et al. Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes. Proc Natl Acad Sci USA 2004; 101: 17120-17125.
53 Zick Y. Uncoupling insulin signalling by serine/ threonine phosphorylation: a molecular basis for insulin resistance. Biochem Soc Trans 2004; 32: 812-816.
54 Smith U, Axelsen M, Carvalho E. et al. Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. Ann NY Acad Sci 1999; 892: 119-126.
55 Cusi K, Maezono K, Osman A. et al. Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000; 105: 311-320.
56 Krook A, Bjornholm M, Galuska D. et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49: 284-292.
57 Shao J, Yamashita H, Qiao L. et al. Decreased Akt kinase activity and insulin resistance in C57BL/KsJLeprdb/db mice. J Endocrinol 2000; 167: 107-115.
58 Olefsky JM, Nolan JJ. Insulin resistance and noninsulin-dependent diabetes mellitus: cellular and molecular mechanisms. Am J Clin Nutr 1995; 61: 980S-986S.
59 Zick Y. Ser/Thr phosphorylation of IRS proteins:a molecular basis for insulin resistance. Sci STKE 2005; 2005: pe4.
60 Herschkovitz A, Liu YF, Ilan E. et al. Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance. J Biol Chem 2007; 282: 18018-18027.
61 Anderson RG. The caveolae membrane system. Annu Rev Biochem 1998; 67: 199-225.
62 Le Lay S, Krief S, Farnier C. et al. Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes. J Biol Chem 2001; 276: 16904-16910.
63 Gille H, Downward J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem 1999; 274: 22033-22040.
64 Brennan P, Babbage JW, Thomas G. et al. p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation inT lymphocytes. Mol Cell Biol 1999; 19: 4729-4738.
65 Koziczak M, Krek W, Nagamine Y. Pocket proteinindependent repression of urokinase-type plasminogen activator and plasminogen activator inhibitor 1 gene expression by E2F1. Mol Cell Biol 2000; 20: 2014-2022.
66 Koziczak M, Muller H, Helin K. et al. E2F1-mediated transcriptional inhibition of the plasminogen activator inhibitor type 1 gene. Eur J Biochem 2001; 268: 4969-4978.
67 Nagamine Y, Medcalf RL, Munoz-Canoves P. Transcriptional and posttranscriptional regulation of the plasminogen activator system. Thromb Haemost 2005; 93: 661-675.
68 Han HJ, Russo J, Kohwi Y. et al. SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature 2008; 452: 187-193.
69 Providence KM, Higgins PJ. PAI-1 expression is required for epithelial cell migration in two distinct phases of in vitro wound repair. J Cell Physiol 2004; 200: 297-308.
70 Vulin AI, Stanley FM. Oxidative stress activates the plasminogen activator inhibitor type 1 (PAI-1) promoter through an AP-1 response element and cooperates with insulin for additive effects on PAI-1 transcription. J Biol Chem 2004; 279: 25172-25178.
71 Liu Q, Moller U, Flugel D. et al. Induction of plasminogen activator inhibitorI gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood 2004; 104: 3993-4001.
72 Parra M, Jardi M, Koziczak M. et al. p53 Phosphorylation at serine 15 is required for transcriptional induction of the plasminogen activator inhibitor-1 (PAI-1) gene by the alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine. J Biol Chem 2001; 276: 36303-36310.
73 Vidal B, Parra M, Jardi M. et al. The alkylating carcinogen N-methyl-N’-nitro-N-nitrosoguanidine activates the plasminogen activator inhibitor-1 gene through sequential phosphorylation of p53 by ATM and ATR kinases. Thromb Haemost 2005; 93: 584-591.
74 Descheemaeker KA, Wyns S, Nelles L. et al. Interaction of AP-1-, AP-2-, and Sp1-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem 1992; 267: 15086-15091.
75 Arts J, Grimbergen J, Bosma PJ. et al. Role of c-Jun and proximal phorbol 12-myristate-13-acetate-(PMA)responsive elements in the regulation of basal and PMA-stimulated plasminogen-activator inhibitor-1 gene expression in HepG2. Eur J Biochem 1996; 241: 393-402.
76 Chen Y, Billadello JJ, Schneider DJ. Identification and localization of a fatty acid response region in the human plasminogen activator inhibitor-1 gene. Arterioscler Thromb Vasc Biol 2000; 20: 2696-2701.
77 Kasza A, Kiss DL, Gopalan S. et al. Mechanism of plasminogen activator inhibitor-1 regulation by oncostatin M and interleukin-1 in human astrocytes. J Neurochem 2002; 83: 696-703.
78 Du XL, Edelstein D, Rossetti L. et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 2000; 97: 12222-12226.
79 Goldberg HJ, Scholey J, Fantus IG. Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells. Diabetes 2000; 49: 863-871.
80 Goldberg HJ, Whiteside CI, Fantus IG. The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-betaI and -delta. J Biol Chem 2002; 277: 33833-33841.
81 Ma Y, Ryu JS, Dulay A. et al. Regulation of plasminogen activator inhibitor (PAI)-1 expression in a human trophoblast cell line by glucocorticoid (GC) and transforming growth factor (TGF)-beta. Placenta 2002; 23: 727-734.
82 Morange PE, Aubert J, Peiretti F. et al. Glucocorticoids and insulin promote plasminogen activator inhibitor1 production by human adipose tissue. Diabetes 1999; 48: 890-895.
83 Healy AM, Gelehrter TD. Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response. J Biol Chem 1994; 269: 19095-19100.
84 Watanabe A, Kanai H, Arai M. et al. Retinoids induce the PAI-1 gene expression through tyrosine kinase-dependent pathways in vascular smooth muscle cells. J Cardiovasc Pharmacol 2002; 39: 503-512.
85 Hou B, Eren M, Painter CA. et al. Tumor necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through a distal nuclear factor kappaB site. J Biol Chem 2004; 279: 18127-18136.
86 Samad F, Yamamoto K, Pandey M. et al. Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol Med 1997; 03: 37-48.
87 Kellouche S, Mourah S, Bonnefoy A. et al. Platelets, thrombospondin-1 and human dermal fibroblasts cooperate for stimulation of endothelial cell tubulogenesis through VEGF and PAI-1 regulation. Exp Cell Res 2007; 313: 486-499.
88 Pontrelli P, Ranieri E, Ursi M. et al. jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells. Kidney Int 2004; 65: 2249-2261.
89 Chen HC, Feener EP. MEK1,2 response element mediates angiotensin II-stimulated plasminogen activator inhibitor-1 promoter activation. Blood 2004; 103: 2636-2644.
90 Motojima M, Ando T, Yoshioka T. Sp1-like activity mediates angiotensin-II-induced plasminogen-activator inhibitor type-1 (PAI-1) gene expression in mesangial cells. Biochem J 2000; 349: 435-441.
91 Olman MA, Hagood JS, Simmons WL. et al. Fibrin fragment induction of plasminogen activator inhibitor transcription is mediated by activator protein-1 through a highly conserved element. Blood 1999; 94: 2029-2038.
92 Schoenhard JA, Smith LH, Painter CA. et al. Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2. J Mol Cell Cardiol 2003; 35: 473-481.
93 Maemura K, de la Monte SM, Chin MT. et al. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression. J Biol Chem 2000; 275: 36847-36851.
94 Wang J, Yin L, Lazar MA. The orphan nuclear receptor Rev-erb alpha regulates circadian expression of plasminogen activator inhibitor type 1. J Biol Chem 2006; 281: 33842-33848.
95 Samarakoon R, Higgins PJ. MEK/ERK pathway mediates cell-shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament and microtubule networks. J Cell Sci 2002; 115: 3093-3103.
96 Grenett HE, Wolkowicz PE, Benza RL. et al. Identification of a 251-bp fragment of the PAI-1 gene promoter that mediates the ethanol-induced suppression of PAI-1 expression. Alcohol Clin Exp Res 2001; 25: 629-636.
97 Cullen JP, Sayeed S, Kim Y. et al. Ethanol inhibits pulse pressure-induced vascular smooth muscle cell migration by differentially modulating plasminogen activator inhibitor type 1, matrix metalloproteinase-2 and -9. Thromb Haemost 2005; 94: 639-645.