Semin Thromb Hemost 2011; 37(4): 395-407
DOI: 10.1055/s-0031-1276589
© Thieme Medical Publishers

Forty Years Later and the Role of Plasminogen Activator Inhibitor Type 2/SERPINB2 Is Still an Enigma

Jodi A. Lee1 , Blake J. Cochran1 , Sergei Lobov1 , Marie Ranson1
  • 1School of Biological Sciences, University of Wollongong, Wollongong NSW, Australia
Further Information

Publication History

Publication Date:
30 July 2011 (online)

ABSTRACT

Plasminogen activator inhibitor (PAI)-2 expression is acutely upregulated in pregnancy, inflammation, infection, and other pathophysiological conditions. Circumstances that prevent PAI-2 upregulation are associated with chronic pathology. Altogether this strongly suggests that PAI-2 is one of the many proteins that maintain homeostasis during damage or stress. However, several functions ranging from a classical serpin to various intracellular roles have been ascribed to PAI-2 and, because none of these have been definitively proven in vivo, to this day its precise role or roles remains an enigma. This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2.

REFERENCES

  • 1 Kawano T, Morimoto K, Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta.  J Biochem. 1970;  67 (3) 333-342
  • 2 Astedt B, Lecander I, Brodin T, Lundblad A, Löw K. Purification of a specific placental plasminogen activator inhibitor by monoclonal antibody and its complex formation with plasminogen activator.  Thromb Haemost. 1985;  53 (1) 122-125
  • 3 Astedt B, Bladh B, Christensen U, Lecander I. Different inhibition of one and two chain tissue plasminogen activator by a placental inhibitor studied with two tripeptide-p-nitroanilide substrates.  Scand J Clin Lab Invest. 1985;  45 (5) 429-435
  • 4 Thorsen S, Philips M, Selmer J, Lecander I, Astedt B. Kinetics of inhibition of tissue-type and urokinase-type plasminogen activator by plasminogen-activator inhibitor type 1 and type 2.  Eur J Biochem. 1988;  175 (1) 33-39
  • 5 Loskutoff D J, Edgington T E. Synthesis of a fibrinolytic activator and inhibitor by endothelial cells.  Proc Natl Acad Sci U S A. 1977;  74 (9) 3903-3907
  • 6 Kruithof E K, Baker M S, Bunn C L. Biological and clinical aspects of plasminogen activator inhibitor type 2.  Blood. 1995;  86 (11) 4007-4024
  • 7 Kruithof E K, Tran-Thang C, Ransijn A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma.  Blood. 1984;  64 (4) 907-913
  • 8 Silverman G A, Bird P I, Carrell R W et al.. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature.  J Biol Chem. 2001;  276 (36) 33293-33296
  • 9 Law R H, Zhang Q, McGowan S et al.. An overview of the serpin superfamily.  Genome Biol. 2006;  7 (5) 216
  • 10 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;  261 (24) 11207-11213
  • 11 Genton C, Kruithof E K, Schleuning W D. Phorbol ester induces the biosynthesis of glycosylated and nonglycosylated plasminogen activator inhibitor 2 in high excess over urokinase-type plasminogen activator in human U-937 lymphoma cells.  J Cell Biol. 1987;  104 (3) 705-712
  • 12 Antalis T M, La Linn M, Donnan K et al.. The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming.  J Exp Med. 1998;  187 (11) 1799-1811
  • 13 Dickinson J L, Bates E J, Ferrante A, Antalis T M. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function.  J Biol Chem. 1995;  270 (46) 27894-27904
  • 14 Dickinson J L, Norris B J, Jensen P H, Antalis T M. The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF-alpha induced apoptosis.  Cell Death Differ. 1998;  5 (2) 163-171
  • 15 Fish R J, Kruithof E K. Evidence for serpinB2-independent protection from TNF-alpha-induced apoptosis.  Exp Cell Res. 2006;  312 (3) 350-361
  • 16 Croucher D, Ranson M, Saunders D. SerpinB2.  In: UCSD nature molecule pages 1.0. In press
  • 17 Medcalf R L, Stasinopoulos S J. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2.  FEBS J. 2005;  272 (19) 4858-4867
  • 18 Croucher D R, Saunders D N, Lobov S, Ranson M. Revisiting the biological roles of PAI2 (SERPINB2) in cancer.  Nat Rev Cancer. 2008;  8 (7) 535-545
  • 19 Ye R D, Ahern S M, Le Beau M M, Lebo R V, Sadler J E. Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin.  J Biol Chem. 1989;  264 (10) 5495-5502
  • 20 Remold-O'Donnell E. The ovalbumin family of serpin proteins.  FEBS Lett. 1993;  315 (2) 105-108
  • 21 Scott F L, Eyre H J, Lioumi M et al.. Human ovalbumin serpin evolution: phylogenic analysis, gene organization, and identification of new PI8-related genes suggest that two interchromosomal and several intrachromosomal duplications generated the gene clusters at 18q21-q23 and 6p25.  Genomics. 1999;  62 (3) 490-499
  • 22 Lobov S, Wilczynska M, Bergström F, Johansson L B, Ny T. Structural bases of the redox-dependent conformational switch in the serpin PAI-2.  J Mol Biol. 2004;  344 (5) 1359-1368
  • 23 Wohlwend A, Belin D, Vassalli J D. Plasminogen activator-specific inhibitors produced by human monocytes/macrophages.  J Exp Med. 1987;  165 (2) 320-339
  • 24 Hamilton J A, Whitty G A, Stanton H et al.. Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes.  Blood. 1993;  82 (12) 3616-3621
  • 25 Ritchie H, Jamieson A, Booth N A. Regulation, location and activity of plasminogen activator inhibitor 2 (PAI-2) in peripheral blood monocytes, macrophages and foam cells.  Thromb Haemost. 1997;  77 (6) 1168-1173
  • 26 Swartz J M, Byström J, Dyer K D, Nitto T, Wynn T A, Rosenberg H F. Plasminogen activator inhibitor-2 (PAI-2) in eosinophilic leukocytes.  J Leukoc Biol. 2004;  76 (4) 812-819
  • 27 Robinson N A, Lapic S, Welter J F, Eckert R L. S100A11, S100A10, annexin I, desmosomal proteins, small proline-rich proteins, plasminogen activator inhibitor-2, and involucrin are components of the cornified envelope of cultured human epidermal keratinocytes.  J Biol Chem. 1997;  272 (18) 12035-12046
  • 28 Akiyama H, Ikeda K, Kondo H, Kato M, McGeer P L. Microglia express the type 2 plasminogen activator inhibitor in the brain of control subjects and patients with Alzheimer's disease.  Neurosci Lett. 1993;  164 (1–2) 233-235
  • 29 Kruithof E K, Tran-Thang C, Gudinchet A et al.. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors.  Blood. 1987;  69 (2) 460-466
  • 30 Ritchie H, Booth N A. The distribution of the secreted and intracellular forms of plasminogen activator inhibitor 2 (PAI-2) in human peripheral blood monocytes is modulated by serum.  Thromb Haemost. 1998;  79 (4) 813-817
  • 31 Gettins P GW. Serpin structure, mechanism, and function.  Chem Rev. 2002;  102 (12) 4751-4804
  • 32 Huntington J A. Shape-shifting serpins—advantages of a mobile mechanism.  Trends Biochem Sci. 2006;  31 (8) 427-435
  • 33 Schwartz B S. Differential inhibition of soluble and cell surface receptor-bound single-chain urokinase by plasminogen activator inhibitor type 2. A potential regulatory mechanism.  J Biol Chem. 1994;  269 (11) 8319-8323
  • 34 Wojta J, Hoover R L, Daniel T O. Vascular origin determines plasminogen activator expression in human endothelial cells. Renal endothelial cells produce large amounts of single chain urokinase type plasminogen activator.  J Biol Chem. 1989;  264 (5) 2846-2852
  • 35 Leung K C, Byatt J A, Stephens R W. The resistance of fibrin-stimulated tissue plasminogen activator to inactivation by a class PAI-2 inhibitor (minactivin).  Thromb Res. 1987;  46 (6) 755-766
  • 36 Ritchie H, Lawrie L C, Mosesson M W, Booth N A. Characterization of crosslinking sites in fibrinogen for plasminogen activator inhibitor 2 (PAI-2).  Ann N Y Acad Sci. 2001;  936 215-218
  • 37 Leung K C, Byatt J A, Stephens R W. Poly-D-lysine dependent inactivation of tissue plasminogen activator by a class PAI-2 inhibitor (minactivin).  Thromb Res. 1987;  46 (6) 767-777
  • 38 Lobov S, Croucher D R, Saunders D N, Ranson M. Plasminogen activator inhibitor type 2 inhibits cell surface associated tissue plasminogen activator in vitro: potential receptor interactions.  Thromb Haemost. 2008;  100 (2) 319-329
  • 39 Lee J A, Croucher D R, Ranson M. Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI-2 on human peripheral blood monocytes.  Thromb Haemost. 2010;  104 (6) 1133-1142
  • 40 Al-Ejeh F, Croucher D, Ranson M. Kinetic analysis of plasminogen activator inhibitor type-2: urokinase complex formation and subsequent internalisation by carcinoma cell lines.  Exp Cell Res. 2004;  297 (1) 259-271
  • 41 Lecander I, Astedt B. Specific plasminogen activator inhibitor of placental type PAI 2 occurring in amniotic fluid and cord blood.  J Lab Clin Med. 1987;  110 (5) 602-605
  • 42 Astedt B, Lindoff C, Lecander I. Significance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy.  Semin Thromb Hemost. 1998;  24 (5) 431-435
  • 43 Booth N A, Reith A, Bennett B. A plasminogen activator inhibitor (PAI-2) circulates in two molecular forms during pregnancy.  Thromb Haemost. 1988;  59 (1) 77-79
  • 44 Kinnby B. The plasminogen activating system in periodontal health and disease.  Biol Chem. 2002;  383 (1) 85-92
  • 45 Virtanen O J, Sirén V, Multanen J et al.. Plasminogen activators and their inhibitors in human saliva and salivary gland tissue.  Eur J Oral Sci. 2006;  114 (1) 22-26
  • 46 Scott-Coombes D, Whawell S, Vipond M N, Thompson J. Human intraperitoneal fibrinolytic response to elective surgery.  Br J Surg. 1995;  82 (3) 414-417
  • 47 Alemán C, Alegre J, Monasterio J et al.. Association between inflammatory mediators and the fibrinolysis system in infectious pleural effusions.  Clin Sci (Lond). 2003;  105 (5) 601-607
  • 48 Csutak A, Silver D M, Tozsér J et al.. Plasminogen activator inhibitor in human tears after laser refractive surgery.  J Cataract Refract Surg. 2008;  34 (6) 897-901
  • 49 Scherrer A, Kruithof E K, Grob J P. Plasminogen activator inhibitor-2 in patients with monocytic leukemia.  Leukemia. 1991;  5 (6) 479-486
  • 50 Robbie L A, Dummer S, Booth N A, Adey G D, Bennett B. Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis.  Br J Haematol. 2000;  109 (2) 342-348
  • 51 Lecander I, Martinsson G, Casslén B et al.. Occurrence of the specific plasminogen activator inhibitor of placental type, PAI-2 in ascitic fluid and tumour vessel blood from patients with ovarian carcinoma.  Fibrinolysis. 1990;  4 (4) 221-224
  • 52 Varro A, Hemers E, Archer D et al.. Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: role of Rho GTPase and menin.  Gastroenterology. 2002;  123 (1) 271-280
  • 53 Coolman M, de Groot C J, Steegers E A et al.. Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy.  Eur J Obstet Gynecol Reprod Biol. 2006;  128 (1-2) 22-28
  • 54 Hunt B J, Missfelder-Lobos H, Parra-Cordero M et al.. Pregnancy outcome and fibrinolytic, endothelial and coagulation markers in women undergoing uterine artery Doppler screening at 23 weeks.  J Thromb Haemost. 2009;  7 (6) 955-961
  • 55 Brenner B. Haemostatic changes in pregnancy.  Thromb Res. 2004;  114 (5–6) 409-414
  • 56 Reith A, Booth N A, Moore N R, Cruickshank D J, Bennett B. Plasminogen activator inhibitors (PAI-1 and PAI-2) in normal pregnancies, pre-eclampsia and hydatidiform mole.  Br J Obstet Gynaecol. 1993;  100 (4) 370-374
  • 57 Kiso U, Henschen A, Bohn H et al.. Identity between the placental protein PP10 and the specific plasminogen activator inhibitor of placental type PAI-2.  Biochim Biophys Acta. 1991;  1074 (1) 74-78
  • 58 Nakashima A, Kobayashi T, Terao T. Fibrinolysis during normal pregnancy and severe preeclampsia relationships between plasma levels of plasminogen activators and inhibitors.  Gynecol Obstet Invest. 1996;  42 (2) 95-101
  • 59 Brown J M, Watanabe K, Cohen R L, Chambers D A. Molecular characterization of plasminogen activators in human gingival crevicular fluid.  Arch Oral Biol. 1995;  40 (9) 839-845
  • 60 Yin X, Bunn C L, Bartold P M. Detection of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 2(PAI-2) in gingival crevicular fluid from healthy, gingivitis and periodontitis patients.  J Clin Periodontol. 2000;  27 (3) 149-156
  • 61 Saunders D N, Buttigieg K M, Gould A, McPhun V, Baker M S. Immunological detection of conformational neoepitopes associated with the serpin activity of plasminogen activator inhibitor type-2.  J Biol Chem. 1998;  273 (18) 10965-10971
  • 62 Lindberg P, Baker M S, Kinnby B. The localization of the relaxed form of plasminogen activator inhibitor type 2 in human gingival tissues.  Histochem Cell Biol. 2001;  116 (5) 447-452
  • 63 Baker M S, Green S P, Goss N, Katrantzis M, Doe W F. Plasminogen activator inhibitor 2 (PAI-2) is not inactivated by exposure to oxidants which can be released from activated neutrophils.  Biochem Biophys Res Commun. 1990;  166 (2) 993-1000
  • 64 Bouchet C, Hacène K, Martin P M et al.. Dissemination risk index based on plasminogen activator system components in primary breast cancer.  J Clin Oncol. 1999;  17 (10) 3048-3057
  • 65 Foekens J A, Peters H A, Look M P et al.. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients.  Cancer Res. 2000;  60 (3) 636-643
  • 66 Pedersen A N, Brünner N, Høyer-Hansen G et al.. Determination of the complex between urokinase and its type-1 inhibitor in plasma from healthy donors and breast cancer patients.  Clin Chem. 1999;  45 (8 Pt 1) 1206-1213
  • 67 Sten-Linder M, Seddighzadeh M, Engel G et al.. Prognostic importance of the uPa/PAI-1 complex in breast cancer.  Anticancer Res. 2001;  21 (4B) 2861-2865
  • 68 Zhang S J, Zou M, Lu L et al.. Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity.  PLoS Genet. 2009;  5 (8) e1000604
  • 69 Byström J, Wynn T A, Domachowske J B, Rosenberg H F. Gene microarray analysis reveals interleukin-5-dependent transcriptional targets in mouse bone marrow.  Blood. 2004;  103 (3) 868-877
  • 70 Park J M, Greten F R, Wong A et al.. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis—CREB and NF-kappaB as key regulators.  Immunity. 2005;  23 (3) 319-329
  • 71 Greten F R, Arkan M C, Bollrath J et al.. NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.  Cell. 2007;  130 (5) 918-931
  • 72 Sekine H, Mimura J, Oshima M et al.. Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock.  Mol Cell Biol. 2009;  29 (24) 6391-6400
  • 73 Jensen P H, Fladmark K E, Gjertsen B T, Vintermyr O K. Caspase I-related protease inhibition retards the execution of okadaic acid- and camptothecin-induced apoptosis and PAI-2 cleavage, but not commitment to cell death in HL-60 cells.  Br J Cancer. 1999;  79 (11-12) 1685-1691
  • 74 Schroder W A, Le T T, Major L et al.. A physiological function of inflammation-associated SerpinB2 is regulation of adaptive immunity.  J Immunol. 2010;  184 (5) 2663-2670
  • 75 Krishnamurti C, Wahl L M, Alving B M. Stimulation of plasminogen activator inhibitor activity in human monocytes infected with dengue virus.  Am J Trop Med Hyg. 1989;  40 (1) 102-107
  • 76 Krishnamurti C, Alving B. Effect of dengue virus on procoagulant and fibrinolytic activities of monocytes.  Rev Infect Dis. 1989;  11 (Suppl 4) S843-S846
  • 77 Losick V P, Isberg R R. NF-kappaB translocation prevents host cell death after low-dose challenge by Legionella pneumophila .  J Exp Med. 2006;  203 (9) 2177-2189
  • 78 Haile W B, Coleman J L, Benach J L. Reciprocal upregulation of urokinase plasminogen activator and its inhibitor, PAI-2, by Borrelia burgdorferi affects bacterial penetration and host-inflammatory response.  Cell Microbiol. 2006;  8 (8) 1349-1360
  • 79 Gan H, Newman G W, Remold H G. Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4.  J Immunol. 1995;  155 (3) 1304-1315
  • 80 Loeffler J, Haddad Z, Bonin M et al.. Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus. .  J Med Microbiol. 2009;  58 (Pt 1) 49-58
  • 81 Silverman G A, Jockel J I, Domer P H, Mohr R M, Taillon-Miller P, Korsmeyer S J. Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2.  Genomics. 1991;  9 (2) 219-228
  • 82 Jensen P H, Cressey L I, Gjertsen B T et al.. Cleaved intracellular plasminogen activator inhibitor 2 in human myeloleukaemia cells is a marker of apoptosis.  Br J Cancer. 1994;  70 (5) 834-840
  • 83 Zhou H M, Bolon I, Nichols A, Wohlwend A, Vassalli J D. Overexpression of plasminogen activator inhibitor type 2 in basal keratinocytes enhances papilloma formation in transgenic mice.  Cancer Res. 2001;  61 (3) 970-976
  • 84 Zhang Y Q, Li P, Hou M et al.. Identification of interaction between PAI-2 and IRF-3.  Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003;  35 (7) 661-665
  • 85 Fan J, Zhang Y Q, Li P et al.. Interaction of plasminogen activator inhibitor-2 and proteasome subunit, beta type 1.  Acta Biochim Biophys Sin (Shanghai). 2004;  36 (1) 42-46
  • 86 Jensen P H, Jensen T G, Laug W E, Hager H, Gliemann J, Pepinsky B. The exon 3 encoded sequence of the intracellular serine proteinase inhibitor plasminogen activator inhibitor 2 is a protein binding domain.  J Biol Chem. 1996;  271 (43) 26892-26899
  • 87 Jensen P H, Schüler E, Woodrow G et al.. A unique interhelical insertion in plasminogen activator inhibitor-2 contains three glutamines, Gln83, Gln84, Gln86, essential for transglutaminase-mediated cross-linking.  J Biol Chem. 1994;  269 (21) 15394-15398
  • 88 Ritchie H, Robbie L A, Kinghorn S, Exley R, Booth N A. Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin.  Thromb Haemost. 1999;  81 (1) 96-103
  • 89 Mikus P, Ny T. Intracellular polymerization of the serpin plasminogen activator inhibitor type 2.  J Biol Chem. 1996;  271 (17) 10048-10053
  • 90 Wilczynska M, Lobov S, Ohlsson P I, Ny T. A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization.  EMBO J. 2003;  22 (8) 1753-1761
  • 91 Darnell G A, Antalis T M, Johnstone R W et al.. Inhibition of retinoblastoma protein degradation by interaction with the serpin plasminogen activator inhibitor 2 via a novel consensus motif.  Mol Cell Biol. 2003;  23 (18) 6520-6532
  • 92 Darnell G A, Antalis T M, Rose B R, Suhrbier A. Silencing of integrated human papillomavirus type 18 oncogene transcription in cells expressing SerpinB2.  J Virol. 2005;  79 (7) 4246-4256
  • 93 Syrjänen S, Naud P, Sarian L et al.. Up-regulation of plasminogen activator inhibitor-2 is associated with high-risk HPV and grade of cervical lesion at baseline but does not predict outcomes of high-risk HPV infections or incident CIN.  Am J Clin Pathol. 2009;  132 (6) 883-892
  • 94 Darnell G A, Schroder W A, Gardner J et al.. SerpinB2 is an inducible host factor involved in enhancing HIV-1 transcription and replication.  J Biol Chem. 2006;  281 (42) 31348-31358
  • 95 Mikus P, Urano T, Liljeström P, Ny T. Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms.  Eur J Biochem. 1993;  218 (3) 1071-1082
  • 96 Wilczynska M, Lobov S, Ny T. The spontaneous polymerization of plasminogen activator inhibitor type-2 and Z-antitrypsin are due to different molecular aberrations.  FEBS Lett. 2003;  537 (1–3) 11-16
  • 97 Stein P E, Carrell R W. What do dysfunctional serpins tell us about molecular mobility and disease?.  Nat Struct Biol. 1995;  2 (2) 96-113
  • 98 Davis R L, Shrimpton A E, Holohan P D et al.. Familial dementia caused by polymerization of mutant neuroserpin.  Nature. 1999;  401 (6751) 376-379
  • 99 Whisstock J C, Bottomley S P. Structural biology: Serpins' mystery solved.  Nature. 2008;  455 (7217) 1189-1190
  • 100 Almeida-Vega S, Catlow K, Kenny S, Dimaline R, Varro A. Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1.  Am J Physiol Gastrointest Liver Physiol. 2009;  296 (2) G414-G423
  • 101 Cousin E, Medcalf R L, Bergonzelli G E, Kruithof E K. Regulatory elements involved in constitutive and phorbol ester-inducible expression of the plasminogen activator inhibitor type 2 gene promoter.  Nucleic Acids Res. 1991;  19 (14) 3881-3886
  • 102 Mahony D, Kalionis B, Antalis T M. Plasminogen activator inhibitor type-2 (PAI-2) gene transcription requires a novel NF-kappaB-like transcriptional regulatory motif.  Eur J Biochem. 1999;  263 (3) 765-772
  • 103 Schuster W A, Medcalf R L, Kruithof E KO. Localization and characterisation of a retinoic acid response-like element in the plasminogen activator inhibitor-2 gene promoter.  Fibrinolysis. 1994;  8 113-119
  • 104 Schuster W A, Medcalf R L, Kruithof E K. Retinoic acid potentiates phorbol ester-mediated induction of urokinase and plasminogen activator inhibitor type 2 in human myeloid leukemic cell lines.  Endocrinology. 1993;  133 (4) 1724-1730
  • 105 Sutter T R, Guzman K, Dold K M, Greenlee W F. Targets for dioxin: genes for plasminogen activator inhibitor-2 and interleukin-1 beta.  Science. 1991;  254 (5030) 415-418
  • 106 Antalis T M, Costelloe E, Muddiman J, Ogbourne S, Donnan K. Regulation of the plasminogen activator inhibitor type-2 gene in monocytes: localization of an upstream transcriptional silencer.  Blood. 1996;  88 (10) 3686-3697
  • 107 Dear A E, Shen Y, Rüegg M, Medcalf R L. Molecular mechanisms governing tumor-necrosis-factor-mediated regulation of plasminogen-activator inhibitor type-2 gene expression.  Eur J Biochem. 1996;  241 (1) 93-100
  • 108 Ogbourne S M, Antalis T M. Characterisation of PAUSE-1, a powerful silencer in the human plasminogen activator inhibitor type 2 gene promoter.  Nucleic Acids Res. 2001;  29 (19) 3919-3927
  • 109 Maurer F, Tierney M, Medcalf R L. An AU-rich sequence in the 3′-UTR of plasminogen activator inhibitor type 2 (PAI-2) mRNA promotes PAI-2 mRNA decay and provides a binding site for nuclear HuR.  Nucleic Acids Res. 1999;  27 (7) 1664-1673
  • 110 Maurer F, Medcalf R L. Plasminogen activator inhibitor type 2 gene induction by tumor necrosis factor and phorbol ester involves transcriptional and post-transcriptional events. Identification of a functional nonameric AU-rich motif in the 3′-untranslated region.  J Biol Chem. 1996;  271 (42) 26074-26080
  • 111 Yu H, Stasinopoulos S, Leedman P, Medcalf R L. Inherent instability of plasminogen activator inhibitor type 2 mRNA is regulated by tristetraprolin.  J Biol Chem. 2003;  278 (16) 13912-13918
  • 112 Tierney M J, Medcalf R L. Plasminogen activator inhibitor type 2 contains mRNA instability elements within exon 4 of the coding region. Sequence homology to coding region instability determinants in other mRNAs.  J Biol Chem. 2001;  276 (17) 13675-13684
  • 113 Dougherty K M, Pearson J M, Yang A Y, Westrick R J, Baker M S, Ginsburg D. The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival.  Proc Natl Acad Sci U S A. 1999;  96 (2) 686-691
  • 114 Ong K, Horsfall W, Conway E M, Schuh A C. Early embryonic expression of murine coagulation system components.  Thromb Haemost. 2000;  84 (6) 1023-1030
  • 115 Antalis T M, Clark M A, Barnes T et al.. Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor.  Proc Natl Acad Sci U S A. 1988;  85 (4) 985-989
  • 116 van den Berg E A, le Clercq E, Kooistra T, Frants R R, Bakker E. The human gene for plasminogen activator inhibitor 2 (PAI2) exhibits an EcoRI RFLP.  Nucleic Acids Res. 1990;  18 (9) 2837
  • 117 Palafox-Sánchez C A, Vázquez-Del Mercado M, Orozco-Barocio G et al.. A functional Ser(413)/Ser(413) PAI-2 polymorphism is associated with susceptibility and damage index score in systemic lupus erythematosus.  Clin Appl Thromb Hemost. 2009;  15 (2) 233-238
  • 118 Vázquez-Del Mercado M, García-Cobian T A, Muñoz Valle J F et al.. Genotype Ser413/Ser of PAI-2 polymorphism Ser413/Cys is associated with anti-phospholipid syndrome and systemic lupus erythematosus in a familial case: comparison with healthy controls.  Scand J Rheumatol. 2007;  36 (3) 206-210
  • 119 Buyru N, Altinisik J, Gurel C B, Ulutin T. PCR-RFLP detection of PAI-2 variants in myocardial infarction.  Clin Appl Thromb Hemost. 2003;  9 (4) 333-336
  • 120 McCarthy J J, Parker A, Salem R GeneQuest Investigators et al. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.  J Med Genet. 2004;  41 (5) 334-341
  • 121 Foy C A, Grant P J. PCR-RFLP detection of PAI-2 gene variants: prevalence in ethnic groups and disease relationship in patients undergoing coronary angiography.  Thromb Haemost. 1997;  77 (5) 955-958
  • 122 Shioji G, Ezura Y, Nakajima T et al.. Nucleotide variations in genes encoding plasminogen activator inhibitor-2 and serine proteinase inhibitor B10 associated with prostate cancer.  J Hum Genet. 2005;  50 (10) 507-515
  • 123 Gibson C S, MacLennan A H, Dekker G A et al.. Genetic polymorphisms and spontaneous preterm birth.  Obstet Gynecol. 2007;  109 (2 Pt 1) 384-391
  • 124 Di Bernardo M C, Matakidou A, Eisen T, Houlston R S. GELCAPS Consortium . Plasminogen activator inhibitor variants PAI-1 A15T and PAI-2 S413C influence lung cancer prognosis.  Lung Cancer. 2009;  65 (2) 237-241
  • 125 Ellis V, Wun T C, Behrendt N, Rønne E, Danø K. Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors.  J Biol Chem. 1990;  265 (17) 9904-9908
  • 126 Medcalf R L, Kruithof E K, Schleuning W D. Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes.  J Exp Med. 1988;  168 (2) 751-759
  • 127 Pytel B A, Peppel K, Baglioni C. Plasminogen activator inhibitor type-2 is a major protein induced in human fibroblasts and SK-MEL-109 melanoma cells by tumor necrosis factor.  J Cell Physiol. 1990;  144 (3) 416-422
  • 128 Gyetko M R, Shollenberger S B, Sitrin R G. Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-gamma and tumor necrosis factor-alpha.  J Leukoc Biol. 1992;  51 (3) 256-263
  • 129 Jang W G, Kim H S, Park K G et al.. Analysis of proteome and transcriptome of tumor necrosis factor alpha stimulated vascular smooth muscle cells with or without alpha lipoic acid.  Proteomics. 2004;  4 (11) 3383-3393
  • 130 Wang Y, Jensen P J. Regulation of the level and glycosylation state of plasminogen activator inhibitor type 2 during human keratinocyte differentiation.  Differentiation. 1998;  63 (2) 93-99
  • 131 Champelovier P, Simon A, Garrel C, Levacher G, Praloran V, Seigneurin D. Is interferon gamma one key of metastatic potential increase in human bladder carcinoma?.  Clin Cancer Res. 2003;  9 (12) 4562-4569
  • 132 Hannocks M J, Oliver L, Gabrilove J L, Wilson E L. Regulation of proteolytic activity in human bone marrow stromal cells by basic fibroblast growth factor, interleukin-1, and transforming growth factor beta.  Blood. 1992;  79 (5) 1178-1184
  • 133 Gyetko M R, Wilkinson C C, Sitrin R G. Monocyte urokinase expression: modulation by interleukins.  J Leukoc Biol. 1993;  53 (5) 598-601
  • 134 Hamilton J A, Wojta J, Gallichio M, McGrath K, Filonzi E L. Contrasting effects of transforming growth factor-beta and IL-1 on the regulation of plasminogen activator inhibitors in human synovial fibroblasts.  J Immunol. 1993;  151 (10) 5154-5161
  • 135 Woodruff P G, Boushey H A, Dolganov G M et al.. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.  Proc Natl Acad Sci U S A. 2007;  104 (40) 15858-15863
  • 136 George F, Pourreau-Schneider N, Arnoux D et al.. Modulation of tPA, PAI-1 and PAI-2 antigen and mRNA levels by EGF in the A431 cell line.  Blood Coagul Fibrinolysis. 1990;  1 (6) 689-693
  • 137 Piquette G N, Crabtree M E, el-Danasouri I, Milki A, Polan M L. Regulation of plasminogen activator inhibitor-1 and -2 messenger ribonucleic acid levels in human cumulus and granulosa-luteal cells.  J Clin Endocrinol Metab. 1993;  76 (2) 518-523
  • 138 Medcalf R L, Van den Berg E, Schleuning W D. Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2.  J Cell Biol. 1988;  106 (3) 971-978
  • 139 Schwartz B S, Bradshaw J D. Regulation of plasminogen activator inhibitor mRNA levels in lipopolysaccharide-stimulated human monocytes. Correlation with production of the protein.  J Biol Chem. 1992;  267 (10) 7089-7094
  • 140 Costelloe E O, Stacey K J, Antalis T M, Hume D A. Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine macrophages. Demonstration of a novel pattern of responsiveness to bacterial endotoxin.  J Leukoc Biol. 1999;  66 (1) 172-182
  • 141 Suzuki T, Hashimoto S, Toyoda N et al.. Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE.  Blood. 2000;  96 (7) 2584-2591
  • 142 Xiao Y, Bartold P M. Modulating effect of serum on the stimulation of plasminogen activator inhibitor 2 production in human gingival fibroblasts by lipopolysaccharide and interleukin-1beta.  J Int Acad Periodontol. 2004;  6 (3) 81-88
  • 143 Niiya K, Taniguchi T, Shinbo M et al.. Different regulation of plasminogen activator inhibitor 2 gene expression by phorbol ester and cAMP in human myeloid leukemia cell line PL-21.  Thromb Haemost. 1994;  72 (1) 92-97
  • 144 Seo E Y, Piao Y J, Kim J S, Suhr K B, Park J K, Lee J H. Identification of calcium-induced genes in HaCaT keratinocytes by polymerase chain reaction-based subtractive hybridization.  Arch Dermatol Res. 2002;  294 (9) 411-418
  • 145 Ahn N S, Hu H, Park J S et al.. Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics.  Mutat Res. 2005;  579 (1–2) 189-199
  • 146 Sharon R, Abramovitz R, Miskin R. Plasminogen mRNA induction in the mouse brain after kainate excitation: codistribution with plasminogen activator inhibitor-2 (PAI-2) mRNA.  Brain Res Mol Brain Res. 2002;  104 (2) 170-175
  • 147 Medcalf R L. Cell- and gene-specific interactions between signal transduction pathways revealed by okadaic acid. Studies on the plasminogen activating system.  J Biol Chem. 1992;  267 (17) 12220-12226
  • 148 Dear A E, Medcalf R L. The novel anti-tumour agent oxamflatin differentially regulates urokinase and plasminogen activator inhibitor type 2 expression and inhibits urokinase-mediated proteolytic activity.  Biochim Biophys Acta. 2000;  1492 (1) 15-22
  • 149 Schleuning W D, Medcalf R L, Hession C, Rothenbühler R, Shaw A, Kruithof E K. Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells.  Mol Cell Biol. 1987;  7 (12) 4564-4567
  • 150 Feener E P, Northrup J M, Aiello L P, King G L. Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells.  J Clin Invest. 1995;  95 (3) 1353-1362
  • 151 Hamaguchi M, Morishita Y, Takahashi I, Ogura M, Takamatsu J, Saito H. FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line.  Blood. 1991;  77 (1) 94-100
  • 152 Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression.  J Biol Chem. 2000;  275 (9) 6580-6585
  • 153 Ritchie H, Jamieson A, Booth N A. Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes.  Blood. 1995;  86 (9) 3428-3435
  • 154 Lundgren C H, Sawa H, Sobel B E, Fujii S. Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy.  Circulation. 1994;  90 (4) 1927-1934
  • 155 Buechler C, Ullrich H, Ritter M et al.. Lipoprotein (a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes.  Blood. 2001;  97 (4) 981-986
  • 156 Braungart E, Magdolen V, Degitz K. Retinoic acid upregulates the plasminogen activator system in human epidermal keratinocytes.  J Invest Dermatol. 2001;  116 (5) 778-784
  • 157 Montemurro P, Barbuti G, Conese M et al.. Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase-induced extracellular proteolysis.  Br J Haematol. 1999;  107 (2) 294-299
  • 158 Wada H, Kaneko T, Wakita Y et al.. Effect of lipoproteins on tissue factor activity and PAI-II antigen in human monocytes and macrophages.  Int J Cardiol. 1994;  47 (1, Suppl) S21-S25
  • 159 Jankova L, Harrop S J, Saunders D N et al.. Crystal structure of the complex of plasminogen activator inhibitor 2 with a peptide mimicking the reactive center loop.  J Biol Chem. 2001;  276 (46) 43374-43382
  • 160 DeLano W L. The PyMOL Molecular Graphics System. San Carlos, CA: DeLano Scientific; 2002

Marie RansonPh.D. 

School of Biological Sciences, University of Wollongong, Northfields Avenue

Wollongong NSW 2522, Australia

Email: mranson@uow.edu.au

    >