Thromb Haemost 2003; 89(06): 959-966
DOI: 10.1055/s-0037-1613396
Review Article
Schattauer GmbH

Posttranscriptional regulation of PAI-1 gene expression

Joanne H. Heaton
1   Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Wendy M. Dlakic
1   Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Thomas D. Gelehrter
1   Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
2   Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
› Author Affiliations
Financial support: This work was supported by Public Health Service Grant CA22729 from the National Cancer Institute (to T.D.G.). We also acknowledge National Institutes of Health grants 5 P30 CA46592 to the University of Michigan Comprehensive Cancer Center and 5 P60 DK-20572 to the University of Michigan Diabetes Research and Training Center for support of core services.
Further Information

Publication History

Received 31 December 2002

Accepted after revision 05 March 2003

Publication Date:
08 December 2017 (online)

Summary

The plasminogen activator-plasmin cascade is involved in multiple physiological and pathological processes including fibrinolysis, wound healing, fibrosis, angiogenesis, embryo implantation and tumor cell invasion and metastasis. Plasminogen activator-inhibitor type 1 (PAI-1) is the major physiological regulator of plasminogen activation. PAI-1 is expressed in a variety of mammalian cells and is regulated by growth factors, cytokines and hormones, including agents that elevate cAMP levels. Although cyclic nucleotide regulation of PAI-1 is observed in diverse cell types in various species, including human, limited studies have addressed the mechanism of this regulation. Here we review our work on the regulation of PAI-1 mRNA degradation in HTC rat hepatoma cells, describing the cis-acting cAMP-responsive sequence in the transcript and a novel RNA binding protein that interacts with it. Potential mechanisms by which this RNA-binding protein may be involved in cyclic nucleotide regulation of mRNA stability are discussed and cAMP regulation of PAI-1 in other systems is summarized.

Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

 
  • References

  • 1 Vassalli JD, Pepper MS. Tumour biology. Membrane proteases in focus. Nature 1994; 370: 14-15.
  • 2 Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
  • 3 Huber K. Plasminogen activator inhibitor type-1 (part one): basic mechanisms, regulation, and role for thromboembolic disease. J Thromb Thrombolysis 2001; 11: 183-93.
  • 4 Heaton JH, Gelehrter TD. Glucocorticoid induction of plasminogen activator and plasminogen activator-inhibitor messenger RNA in rat hepatoma cells. Mol Endocrinol 1989; 3: 349-55.
  • 5 Bruzdzinski CJ, Johnson MR, Goble CA, Winograd SS, Gelehrter TD. Mechanism of glucocorticoid induction of the rat plasmino-gen activator inhibitor-1 gene in HTC rat hepatoma cells: identification of cisacting regulatory elements. Mol Endocrinol 1993; 7: 1169-77.
  • 6 Fattal PG, Schneider DJ, Sobel BE, Billadello JJ. Post-transcriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin-like growth factor 1. J Biol Chem 1992; 267: 12412-5.
  • 7 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: 19095-100.
  • 8 Barouski-Miller PA, Gelehrter TD. Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells. Proc Natl Acad Sci U S A 1982; 79: 2319-22.
  • 9 Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol 1990; 68: 1-19.
  • 10 Heaton JH, Gelehrter TD. Cyclic nucleotide regulation of plasminogen activator and plasminogen activator-inhibitor messenger RNAs in rat hepatoma cells. Mol Endocrinol 1990; 4: 171-8.
  • 11 Ross J. mRNA stability in mammalian cells. Microbiol Rev 1995; 59: 423-50.
  • 12 Buzby JS, Brewer G, Nugent DJ. Developmental regulation of RNA transcript destabilization by A + U-rich elements is AUF1-dependent. J Biol Chem 1999; 274: 33973-8.
  • 13 Chkheidze AN, Lyakhov DL, Makeyev AV, Morales J, Kong J, Liebhaber SA. Assembly of the alpha-globin mRNA stability complex reflects binary interaction between the pyrimidine-rich 3’untranslated region determinant and poly(C) binding protein alphaCP. Mol Cell Biol 1999; 19: 4572-81.
  • 14 Malter JS. Regulation of mRNA stability in the nervous system and beyond. J Neurosci Res 2001; 66: 311-6.
  • 15 Perrone-Bizzozero N, Bolognani F. Role of HuD and other RNA-binding proteins in neural development and plasticity. J Neurosci Res 2002; 68: 121-6.
  • 16 Zhang M, Pierce RA, Wachi H, Mecham RP, Parks WC. An open reading frame element mediates posttranscriptional regulation of tropoelastin and responsiveness to transforming growth factor beta1. Mol Cell Biol 1999; 19: 7314-26.
  • 17 Brennan CM, Steitz JA. HuR and mRNA stability. Cell Mol Life Sci 2001; 58: 266-277.
  • 18 Chen CY, Shyu AB. AU-rich elements: char-acterization and importance in mRNA degradation. Trends Biochem Sci 1995; 20: 46570
  • 19 Guhaniyogi J, Brewer G. Regulation of mRNA stability in mammalian cells. Gene 2001; 265: 11-23.
  • 20 Heaton JH, Kathju S, Gelehrter TD. Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides. Mol Endocrinol 1992; 6: 53-60.
  • 21 Heaton JH, Tillmann-Bogush M, Leff NS, Gelehrter TD. Cyclic nucleotide regulation of type-1 plasminogen activator-inhibitor mRNA stability in rat hepatoma cells. Identification of cis-acting sequences. J Biol Chem 1998; 273: 14261-8.
  • 22 Tillmann-Bogush M, Heaton JH, Gelehrter TD. Cyclic nucleotide regulation of PAI-1 mRNA stability. Identification of cytosolic proteins that interact with an a-rich sequence. J Biol Chem 1999; 274: 1172-9.
  • 23 Heaton JH, Dlakic WM, Dlakic M, Gelehrter TD. Identification and cDNA cloning of a novel RNA-binding protein that interacts with the cyclic nucleotide-responsive sequence in the Type-1 plasminogen activator inhibitor mRNA. J Biol Chem 2001; 276: 3341-7.
  • 24 Caudy AA, Myers M, Hannon GJ, Hammond SM. Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev 2002; 16: 2491-6.
  • 25 Fan XC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. Embo J 1998; 17: 3448-60.
  • 26 Loflin P, Chen CY, Shyu AB. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev 1999; 13: 1884-97.
  • 27 Wang W, Furneaux H, Cheng H, Caldwell MC, Hutter D, Liu Y. et al. HuR regulates p21 mRNA stabilization by UV light. Mol Cell Biol 2000; 20: 760-9.
  • 28 Montminy M. Transcriptional regulation by cyc-lic AMP. Annu Rev Biochem 1997; 66: 807-22.
  • 29 Torchia J, Glass C, Rosenfeld MG. Co-activators and co-repressors in the integration of transcriptional responses. Curr Opin Cell Biol 1998; 10: 373-83.
  • 30 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 U S A 1999; 96: 11776-81.
  • 31 Karin M. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?. Cell 1998; 93: 487-90.
  • 32 Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y. Homeodomain-interacting protein kinases, a novel family of corepressors for homeodo-main transcription factors. J Biol Chem 1998; 273: 25875-9.
  • 33 Rydholm H, Bostrom S, Eriksson E, Risberg B. Complex intracellular signal transduction regulates tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) synthesis in cultured human umbilical vein endothelium. Scand J Clin Lab Invest 1995; 55: 323-30.
  • 34 Santell L, Levin EG. Cyclic AMP potentiates phorbol ester stimulation of tissue plasmino-gen activator release and inhibits secretion of plasminogen activator inhibitor-1 from human endothelial cells. J Biol Chem 1988; 263: 16802-8.
  • 35 Slivka SR, Loskutoff DJ. Regulation of type I plasminogen activator inhibitor synthesis by protein kinase C and cAMP in bovine aortic endothelial cells. Biochim Biophys Acta 1991; 1094: 317-22.
  • 36 Zidovetzki R, Wang JL, Kim JA, Chen P, Fisher M, Hofman FM. Endothelin-1 enhances plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-dependent pathway. Arterioscler Thromb Vasc Biol 1999; 19: 1768-75.
  • 37 Konkle BA, Kollros PR, Kelly MD. Heparin-binding growth factor-1 modulation of plasminogen activator inhibitor-1 expression. Interaction with cAMP and protein kinase C- mediated pathways. J Biol Chem 1990; 265: 21867-73.
  • 38 Sugano T, Tsuji H, Masuda H, Nishimura H, Yoshizumi M, Kawano H. et al. Adrenomedullin inhibits angiotensin II-induced expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat aortic endothelial cells. Arterioscler Thromb Vasc Biol 2001; 21: 1078-83.
  • 39 Bergonzelli GE, Kruithof EK, Medcalf RL. Transcriptional antagonism of phorbol ester-mediated induction of plasminogen activator inhibitor types 1 and 2 by cyclic adenosine 3’,5’- monophosphate. Endocrinology 1992; 131: 1467-72.
  • 40 DiBattista JA, Martel-Pelletier J, Morin N, Jolicoeur FC, Pelletier JP. Transcriptional regulation of plasminogen activator inhibitor-1 expression in human synovial fibroblasts by prostaglandin E2: mediation by protein kinase A and role of interleukin-1. Mol Cell Endocrinol 1994; 103: 139-48.
  • 41 Georg B, Riccio A, Andreasen P. Forskolin down-regulates type-1 plasminogen activator inhibitor and tissue-type plasminogen activator and their mRNAs in human fibrosarcoma cells. Mol Cell Endocrinol 1990; 72: 103-10.
  • 42 Thalacker FW, Nilsen-Hamilton M. Opposite and independent actions of cyclic AMP and transforming growth factor beta in the regulation of type 1 plasminogen activator inhibitor expression. Biochem J 1992; 287: 855-62.
  • 43 Lau HK, Ho J. Regulation of plasminogen activator inhibitor-1 secretion by urokinase and tissue plasminogen activator in rat epithelioid-type smooth muscle cells. Br J Haematol 2002; 117: 151-8.
  • 44 Ren S, Cockell KA, Fenton JW 2nd, Angel A, Shen GX. G proteins and phospholipase C mediate thrombin-induced generation of plasminogen activator inhibitor-1 from vascular smooth muscle cells. J Vasc Res 1997; 34: 82-9.
  • 45 Le Magueresse-Battistoni B, Pernod G, Sigillo F, Kolodie L, Benahmed M. Plasminogen activator inhibitor-1 is expressed in cultured rat Sertoli cells. Biol Reprod 1998; 59: 591-8.
  • 46 Liu YX, Liu K, Zhou HM, Du Q, Hu ZY, Zou RJ. Hormonal regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 in cultured monkey Sertoli cells. Hum Reprod 1995; 10: 719-27.
  • 47 Fukumoto S, Allan EH, Yee JA, Gelehrter TD, Martin TJ. Plasminogen activator regulation in osteoblasts: parathyroid hormone inhibition of type-1 plasminogen activator inhibitor and its mRNA. J Cell Physiol 1992; 152: 346-55.
  • 48 Tranque P, Robbins R, Naftolin F, Andrade-Gordon P. Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes. Glia 1992; 6: 163-71.
  • 49 Nargolwalla C, McCabe D, Fritz IB. Modulation of levels of messenger RNA for tissue-type plasminogen activator in rat Sertoli cells, and levels of messenger RNA for plasminogen activator inhibitor in testis peritubular cells. Mol Cell Endocrinol 1990; 70: 73-80.
  • 50 Liu YX, Peng XR, Liu HZ, Chen YJ, Ny T. Prolactin regulation of tissue type plasmino-gen activator and plasminogen activator inhibitor type-I gene expression in eCG-primed rat granulosa cells in culture. Biol Reprod 1998; 59: 409-16.
  • 51 Bator JM, Cohen RL, Chambers DA. Hydro-cortisone regulates the dynamics of plasminogen activator and plasminogen activator inhibitor expression in cultured murine keratinocytes. Exp Cell Res 1998; 242: 110-9.
  • 52 Heaton JH, Nebes VL, O’Dell LG, Morris Jr. SM, 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: 185-92.
  • 53 Uno S, Nakamura M, Seki T, Ariga T. Induction of tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) as early growth responses in rat hepatocytes in primary culture. Biochem Biophys Res Commun 1997; 239: 123-8.
  • 54 Uno S, Nakamura M, Ohomagari Y, Matsuyama S, Seki T, Ariga T. Regulation of tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) gene expression in rat hepatocytes in primary culture. J Biochem (Tokyo) 1998; 123: 806-12.
  • 55 Lijnen HR, Juhan-Vague I. The fibrinolytic system and obesity. Thromb Haemost 2002; 88: 882
  • 56 Juhan-Vague I, Alessi MC, Morange PE. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 2000; 32 (Suppl. 01) 78-84.
  • 57 Seki T, Miyasu T, Noguchi T, Hamasaki A, Sasaki R, Ozawa Y. et al. Reciprocal regulation of tissue-type and urokinase-type plasminogen activators in the differentiation of murine preadipocyte line 3T3-L1 and the hormonal regulation of fibrinolytic factors in the mature adipocytes. J Cell Physiol 2001; 189: 72-8.
  • 58 Halleux CM, Declerck PJ, Tran SL, Detry R, Brichard SM. Hormonal control of plasmino-gen activator inhibitor-1 gene expression and production in human adipose tissue: stimulation by glucocorticoids and inhibition by catecholamines. J Clin Endocrinol Metab 1999; 84: 4097-105.
  • 59 Gottschling-Zeller H, Aprath I, Skurk T, Hauner H. Beta-Adrenoceptor agonists and other cAMP elevating agents suppress PAI- 1 production of human adipocytes in primary culture. Horm Metab Res 2000; 32: 509-14.
  • 60 Knudsen H, Olesen T, Riccio A, Ungaro P, Christensen L, Andreasen PA. A common response element mediates differential effects of phorbol esters and forskolin on type-1 plasminogen activator inhibitor gene expression in human breast carcinoma cells. Eur J Biochem 1994; 220: 63-74.
  • 61 Shetty S, Idell S. Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung carcinoma cells in vitro. Am J Physiol Lung Cell Mol Physiol 2000; 278: L148-156.
  • 62 Stockert RJ. Regulation of the human asialoglycoprotein receptor by cAMP. J Biol Chem 1993; 268: 19540-4.
  • 63 Smith JD, Liu AY. Increased turnover of the messenger RNA encoding tyrosine amino-transferase can account for the desensitization and de-induction of tyrosine aminotransferase by 8-bromo-cyclic AMP treatment and removal. Embo J 1988; 7: 3711-6.
  • 64 Wang L, Ma X, Yeh LC, Adamo ML. Differential regulation of IGF-binding protein gene expression by cAMP in rat C6 glioma cells. Endocrinology 2001; 142: 3917-25.
  • 65 Wang X, Nickenig G, Murphy TJ. The vascular smooth muscle type I angiotensin II receptor mRNA is destabilized by cyclic AMP elevating agents. Mol Pharmacol 1997; 52: 781-7.
  • 66 Themmen AP, Blok LJ, Post M. et al. Follitropin receptor down-regulation involves a cAMP-dependent post- transcriptional decrease of receptor mRNA expression. Mol Cell Endocrinol 1991; 78: R7-13.
  • 67 Tholanikunnel BG, Malbon CC. A 20-nucleotide (A + U)-rich element of beta2-adrenergic receptor (beta2AR) mRNA mediates binding to beta2AR-binding protein and is obligate for agonist-induced destabilization of receptor mRNA. J Biol Chem 1997; 272: 11471-8.
  • 68 Danner S, Frank M, Lohse MJ. Agonist regulation of human beta2-adrenergic receptor mRNA stability occurs via a specific AU-rich element. J Biol Chem 1998; 273: 3223-9.
  • 69 Lu DL, Menon KM. 3’ untranslated region-mediated regulation of luteinizing hormone/ human chorionic gonadotropin receptor expression. Biochemistry 1996; 35: 12347-53.
  • 70 Gasperini S, Crepaldi L, Calzetti F. et al. Interleukin-10 and cAMP-elevating agents cooperate to induce suppressor of cytokine signaling-3 via a protein kinase A-independent signal. Eur Cytokine Netw 2002; 13: 47-53.
  • 71 Lee WY, Loflin P, Clancey CJ, Peng H, Lever JE. Cyclic nucleotide regulation of Na+/glucose cotransporter (SGLT1) mRNA stability. Interaction of a nucleocytoplasmic protein with a regulatory domain in the 3’-untranslated region critical for stabilization. J Biol Chem 2000; 275: 33998-4008.
  • 72 Lee B, Laychock SG. Regulation of inositol trisphosphate receptor isoform expression in glucose-desensitized rat pancreatic islets: role of cyclic adenosine 3’,5’-monophosphate and calcium. Endocrinology 2000; 141: 1394-402.
  • 73 Chen M, Schnermann J, Smart AM, Brosius FC, Killen PD, Briggs JP. Cyclic AMP selectively increases renin mRNA stability in cultured juxtaglomerular granular cells. J Biol Chem 1993; 268: 24138-24144.
  • 74 Sinn PL, Sigmund CD. Human renin mRNA stability is increased in response to cAMP in Calu-6 cells. Hypertension 1999; 33: 900-5.
  • 75 El Jamali A, Rachdaoui N, Dib K, Correze C. Cyclic AMP regulation of G(i alpha2) and G(i alpha3) mRNAs and proteins in astroglial cells. J Neurochem 1998; 71: 2271-7.
  • 76 Tian D, Huang D, Brown RC, Jungmann RA. Protein kinase A stimulates binding of multiple proteins to a U-rich domain in the 3’-untranslated region of lactate dehydrogenase A mRNA that is required for the regulation of mRNA stability. J Biol Chem 1998; 273: 28454-60.
  • 77 Nachaliel N, Jain D, Hod Y. A cAMP-regulated RNA-binding protein that interacts with phosphoenolpyruvate carboxykinase (GTP) mRNA. J Biol Chem 1993; 268: 24203-9.
  • 78 Nair AK, Kash JC, Peegel H, Menon KM. Post-transcriptional regulation of luteinizing hormone receptor mRNA in the ovary by a novel mRNA-binding protein. J Biol Chem 2002; 277: 21468-73.
  • 79 Loflin P, Lever JE. HuR binds a cyclic nucleotide-dependent, stabilizing domain in the 3’ untranslated region of Na(+)/glucose cotrans-porter (SGLT1) mRNA. FEBS Lett 2001; 509: 267-71.
  • 80 Blaxall BC, Pellett AC, Wu SC, Pende A, Port JD. Purification and characterization of beta-adrenergic receptor mRNA- binding proteins. J Biol Chem 2000; 275: 4290-7.