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. 1995 Sep 25;23(18):3710–3717. doi: 10.1093/nar/23.18.3710

Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53.

C Kunz 1, S Pebler 1, J Otte 1, D von der Ahe 1
PMCID: PMC307270  PMID: 7479001

Abstract

The ability of p53 to activate or repress transcription suggests that its biological function as tumor suppressor is in part accomplished by regulating a number of genes including such required for inhibition of cell growth. We here give evidence that p53 also may regulate genes responsible for the proteolytic degradation of the extracellular matrix, which is considered a crucial feature for local invasion and metastasis of neoplastic cells. An important and highly regulated cascade of such proteolytic events involves the plasminogen activator system. We show that wild-type p53 represses transcription from the enhancer and promoter of the human urokinase-type (u-PA) and the tissue-type plasminogen activator (t-PA) gene through a non-DNA binding mechanism. Oncogenic mutants lost the repressing activity. In contrast, wild-type but not mutant p53 specifically binds to and activates the promoter of the plasminogen activator inhibitor type-1 (PAI-1) gene. Interestingly, one of the p53 mutants (273his) inhibited PAI-1 promoter activity. Our results suggest that altered function of oncogenic forms of p53 may lead to altered expression of the plasminogen activators and their inhibitor(s) and thus to altered activation of the plasminogen/plasmin system during tumor progression.

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Selected References

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  1. Agoff S. N., Hou J., Linzer D. I., Wu B. Regulation of the human hsp70 promoter by p53. Science. 1993 Jan 1;259(5091):84–87. doi: 10.1126/science.8418500. [DOI] [PubMed] [Google Scholar]
  2. Barak Y., Juven T., Haffner R., Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993 Feb;12(2):461–468. doi: 10.1002/j.1460-2075.1993.tb05678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell S. M., Connolly D. C., Maihle N. J., Degen J. L. Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases. Mol Cell Biol. 1993 Sep;13(9):5888–5897. doi: 10.1128/mcb.13.9.5888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cajot J. F., Bamat J., Bergonzelli G. E., Kruithof E. K., Medcalf R. L., Testuz J., Sordat B. Plasminogen-activator inhibitor type 1 is a potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6939–6943. doi: 10.1073/pnas.87.18.6939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cajot J. F., Schleuning W. D., Medcalf R. L., Bamat J., Testuz J., Liebermann L., Sordat B. Mouse L cells expressing human prourokinase-type plasminogen activator: effects on extracellular matrix degradation and invasion. J Cell Biol. 1989 Aug;109(2):915–925. doi: 10.1083/jcb.109.2.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Crook T., Marston N. J., Sara E. A., Vousden K. H. Transcriptional activation by p53 correlates with suppression of growth but not transformation. Cell. 1994 Dec 2;79(5):817–827. doi: 10.1016/0092-8674(94)90071-x. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Degen S. J., Rajput B., Reich E. The human tissue plasminogen activator gene. J Biol Chem. 1986 May 25;261(15):6972–6985. [PubMed] [Google Scholar]
  10. Donehower L. A., Bradley A. The tumor suppressor p53. Biochim Biophys Acta. 1993 Aug 23;1155(2):181–205. doi: 10.1016/0304-419x(93)90004-v. [DOI] [PubMed] [Google Scholar]
  11. Farmer G., Bargonetti J., Zhu H., Friedman P., Prywes R., Prives C. Wild-type p53 activates transcription in vitro. Nature. 1992 Jul 2;358(6381):83–86. doi: 10.1038/358083a0. [DOI] [PubMed] [Google Scholar]
  12. Fields S., Jang S. K. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990 Aug 31;249(4972):1046–1049. doi: 10.1126/science.2144363. [DOI] [PubMed] [Google Scholar]
  13. Funk W. D., Pak D. T., Karas R. H., Wright W. E., Shay J. W. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol Cell Biol. 1992 Jun;12(6):2866–2871. doi: 10.1128/mcb.12.6.2866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ginsberg D., Mechta F., Yaniv M., Oren M. Wild-type p53 can down-modulate the activity of various promoters. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9979–9983. doi: 10.1073/pnas.88.22.9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gu Y., Turck C. W., Morgan D. O. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature. 1993 Dec 16;366(6456):707–710. doi: 10.1038/366707a0. [DOI] [PubMed] [Google Scholar]
  16. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  17. Hart I. R., Goode N. T., Wilson R. E. Molecular aspects of the metastatic cascade. Biochim Biophys Acta. 1989 Jul 28;989(1):65–84. doi: 10.1016/0304-419x(89)90035-8. [DOI] [PubMed] [Google Scholar]
  18. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  19. Hupp T. R., Meek D. W., Midgley C. A., Lane D. P. Regulation of the specific DNA binding function of p53. Cell. 1992 Nov 27;71(5):875–886. doi: 10.1016/0092-8674(92)90562-q. [DOI] [PubMed] [Google Scholar]
  20. Jackson P., Bos E., Braithwaite A. W. Wild-type mouse p53 down-regulates transcription from different virus enhancer/promoters. Oncogene. 1993 Mar;8(3):589–597. [PubMed] [Google Scholar]
  21. Johnson P., Chung S., Benchimol S. Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin. Mol Cell Biol. 1993 Mar;13(3):1456–1463. doi: 10.1128/mcb.13.3.1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Keijer J., Linders M., van Zonneveld A. J., Ehrlich H. J., de Boer J. P., Pannekoek H. The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance. Blood. 1991 Jul 15;78(2):401–409. [PubMed] [Google Scholar]
  23. Kern S. E., Pietenpol J. A., Thiagalingam S., Seymour A., Kinzler K. W., Vogelstein B. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science. 1992 May 8;256(5058):827–830. doi: 10.1126/science.1589764. [DOI] [PubMed] [Google Scholar]
  24. Kley N., Chung R. Y., Fay S., Loeffler J. P., Seizinger B. R. Repression of the basal c-fos promoter by wild-type p53. Nucleic Acids Res. 1992 Aug 11;20(15):4083–4087. doi: 10.1093/nar/20.15.4083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kristensen P., Pyke C., Lund L. R., Andreasen P. A., Danø K. Plasminogen activator inhibitor-type 1 in Lewis lung carcinoma. Histochemistry. 1990;93(6):559–566. doi: 10.1007/BF00272198. [DOI] [PubMed] [Google Scholar]
  26. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  27. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  28. Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991 Jan 25;64(2):327–336. doi: 10.1016/0092-8674(91)90642-c. [DOI] [PubMed] [Google Scholar]
  29. Liu X., Miller C. W., Koeffler P. H., Berk A. J. The p53 activation domain binds the TATA box-binding polypeptide in Holo-TFIID, and a neighboring p53 domain inhibits transcription. Mol Cell Biol. 1993 Jun;13(6):3291–3300. doi: 10.1128/mcb.13.6.3291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  31. Mack D. H., Vartikar J., Pipas J. M., Laimins L. A. Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53. Nature. 1993 May 20;363(6426):281–283. doi: 10.1038/363281a0. [DOI] [PubMed] [Google Scholar]
  32. Masuda H., Miller C., Koeffler H. P., Battifora H., Cline M. J. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7716–7719. doi: 10.1073/pnas.84.21.7716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Michalovitz D., Halevy O., Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990 Aug 24;62(4):671–680. doi: 10.1016/0092-8674(90)90113-s. [DOI] [PubMed] [Google Scholar]
  34. Mignatti P., Rifkin D. B. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993 Jan;73(1):161–195. doi: 10.1152/physrev.1993.73.1.161. [DOI] [PubMed] [Google Scholar]
  35. Miyashita T., Krajewski S., Krajewska M., Wang H. G., Lin H. K., Liebermann D. A., Hoffman B., Reed J. C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994 Jun;9(6):1799–1805. [PubMed] [Google Scholar]
  36. Montesano R., Pepper M. S., Möhle-Steinlein U., Risau W., Wagner E. F., Orci L. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell. 1990 Aug 10;62(3):435–445. doi: 10.1016/0092-8674(90)90009-4. [DOI] [PubMed] [Google Scholar]
  37. Nerlov C., De Cesare D., Pergola F., Caracciolo A., Blasi F., Johnsen M., Verde P. A regulatory element that mediates co-operation between a PEA3-AP-1 element and an AP-1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells. EMBO J. 1992 Dec;11(12):4573–4582. doi: 10.1002/j.1460-2075.1992.tb05559.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. O'Shea-Greenfield A., Smale S. T. Roles of TATA and initiator elements in determining the start site location and direction of RNA polymerase II transcription. J Biol Chem. 1992 Jan 15;267(2):1391–1402. [PubMed] [Google Scholar]
  39. Okamoto K., Beach D. Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J. 1994 Oct 17;13(20):4816–4822. doi: 10.1002/j.1460-2075.1994.tb06807.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ossowski L., Clunie G., Masucci M. T., Blasi F. In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion. J Cell Biol. 1991 Nov;115(4):1107–1112. doi: 10.1083/jcb.115.4.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pepper M. S., Belin D., Montesano R., Orci L., Vassalli J. D. Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro. J Cell Biol. 1990 Aug;111(2):743–755. doi: 10.1083/jcb.111.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pietenpol J. A., Tokino T., Thiagalingam S., el-Deiry W. S., Kinzler K. W., Vogelstein B. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):1998–2002. doi: 10.1073/pnas.91.6.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Prokocimer M., Rotter V. Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages. Blood. 1994 Oct 15;84(8):2391–2411. [PubMed] [Google Scholar]
  44. Ragimov N., Krauskopf A., Navot N., Rotter V., Oren M., Aloni Y. Wild-type but not mutant p53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif. Oncogene. 1993 May;8(5):1183–1193. [PubMed] [Google Scholar]
  45. Reich R., Thompson E. W., Iwamoto Y., Martin G. R., Deason J. R., Fuller G. C., Miskin R. Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res. 1988 Jun 15;48(12):3307–3312. [PubMed] [Google Scholar]
  46. Riccio A., Lund L. R., Sartorio R., Lania A., Andreasen P. A., Danø K., Blasi F. The regulatory region of the human plasminogen activator inhibitor type-1 (PAI-1) gene. Nucleic Acids Res. 1988 Apr 11;16(7):2805–2824. doi: 10.1093/nar/16.7.2805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Saksela O., Rifkin D. B. Cell-associated plasminogen activation: regulation and physiological functions. Annu Rev Cell Biol. 1988;4:93–126. doi: 10.1146/annurev.cb.04.110188.000521. [DOI] [PubMed] [Google Scholar]
  48. Santhanam U., Ray A., Sehgal P. B. Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7605–7609. doi: 10.1073/pnas.88.17.7605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Schmitz M. L., Baeuerle P. A. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J. 1991 Dec;10(12):3805–3817. doi: 10.1002/j.1460-2075.1991.tb04950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shiio Y., Yamamoto T., Yamaguchi N. Negative regulation of Rb expression by the p53 gene product. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5206–5210. doi: 10.1073/pnas.89.12.5206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Shirakawa F., Saito K., Bonagura C. A., Galson D. L., Fenton M. J., Webb A. C., Auron P. E. The human prointerleukin 1 beta gene requires DNA sequences both proximal and distal to the transcription start site for tissue-specific induction. Mol Cell Biol. 1993 Mar;13(3):1332–1344. doi: 10.1128/mcb.13.3.1332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sullivan L. M., Quigley J. P. An anticatalytic monoclonal antibody to avian plasminogen activator: its effect on behavior of RSV-transformed chick fibroblasts. Cell. 1986 Jun 20;45(6):905–915. doi: 10.1016/0092-8674(86)90565-9. [DOI] [PubMed] [Google Scholar]
  53. Testa J. E., Quigley J. P. The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. Cancer Metastasis Rev. 1990 Dec;9(4):353–367. doi: 10.1007/BF00049524. [DOI] [PubMed] [Google Scholar]
  54. Thut C. J., Chen J. L., Klemm R., Tjian R. p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science. 1995 Jan 6;267(5194):100–104. doi: 10.1126/science.7809597. [DOI] [PubMed] [Google Scholar]
  55. Tsuboi R., Rifkin D. B. Bimodal relationship between invasion of the amniotic membrane and plasminogen activator activity. Int J Cancer. 1990 Jul 15;46(1):56–60. doi: 10.1002/ijc.2910460112. [DOI] [PubMed] [Google Scholar]
  56. Vassalli J. D., Sappino A. P., Belin D. The plasminogen activator/plasmin system. J Clin Invest. 1991 Oct;88(4):1067–1072. doi: 10.1172/JCI115405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Zhan Q., Carrier F., Fornace A. J., Jr Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol. 1993 Jul;13(7):4242–4250. doi: 10.1128/mcb.13.7.4242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. el-Deiry W. S., Kern S. E., Pietenpol J. A., Kinzler K. W., Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992 Apr;1(1):45–49. doi: 10.1038/ng0492-45. [DOI] [PubMed] [Google Scholar]
  59. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

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