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The Role of RNA Binding Proteins in Tumorigenesis

  • Sreerama Shetty
Part of the Endocrine Updates book series (ENDO, volume 16)

Abstract

Posttranscriptional regulatory mechanisms control expression of a variety of genes implicated in the pathogenesis of inflammation, fibrotic repair and neoplasia. Posttranscriptional regulation involves specific interactions between specific mRNA binding sequences that interact with mRNA binding proteins. These cis-trans interactions can either stabilize or destabilize the mRNAs. Of the genes regulated at the posttranscriptional level, components of the uPA-uPAR fibrinolytic system are prominently represented and these pathways could importantly influence the pathogenesis of pulmonary inflammation and neoplasia. uPA, uPAR, and PAI-1 are expressed by lung and pleural mesothelial cells and are implicated in the pathogenesis of remodeling of the injured lung and pleural space and in cancers that occur in these locations. It is now clear that the expression of each of these genes is regulated at the posttranscriptional level and that the regulatory mechanisms involve the interaction of these mRNAs with specific mRNA binding proteins that control mRNA stability.

Keywords

mRNA Stability Posttranscriptional Regulation uPAR Expression Small Airway Epithelial Cell uPAR mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Akashi, M., Shaw, G., Gross, M., Saito, M. and Koerner, H.P. (1991) Role of AUUU sequences in stabilization of granulocyte-macrophage colony stimulating factor RNA in stimulated cells. Blood 78, 2005–2012.PubMedGoogle Scholar
  2. 2.
    Caput, D., Beutler, B., Hortog, K., Thayer, R., Brown-shimer, S. and Cerami, A. (1986) Identification of a common nucleotide sequence in the 3’-untranslated region of mRNA molecules specifying inflammatory mediators. Proc. Natl. Acad. Sci. U.S.A. 83, 1670–1674.PubMedCrossRefGoogle Scholar
  3. 3.
    Shaw, G. and Kamen, R. (1986) A conserved AU sequence from the 3’ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46, 659–667.PubMedCrossRefGoogle Scholar
  4. 4.
    Jones, T.R. and Cole, M.D. (1987) Rapid cytoplasmic turnover of c-myc mRNA: requirement of 3’untranslated sequences. Mol. Cell Biol. 7, 4513–4521.PubMedGoogle Scholar
  5. 5.
    Wilson, T. and Triesman, R. (1988) Removal of poly(A) tail and consequent degradation of c-fos mRNA facilitated by 3’AU-rich sequence. Nature 336, 396–399.PubMedCrossRefGoogle Scholar
  6. 6.
    Casey, J.L., Koeller, D.M., Ramin, V.C., Klausner, R.D., and Hartford, J.B. (1989) Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3’untranslated region of the mRNA. EMBO J. 12, 3693–3699.Google Scholar
  7. 7.
    Mullner, E.W. and Kuhn, L.C. (1988) A stem-loop in the 3’UTR mediates iron-dependent regulaton of transferrin receptor mRNA stability in the cytoplasm. Cell 53, 815–825.PubMedCrossRefGoogle Scholar
  8. 8.
    Yamato, K., El-Hajjaoui, Z., Kuo, J. and Koeffler, H.P. (1989) Granulocyte-macrophage colony stimulating factor: signals for its mRNA accumulation. Blood 74: 1314–1320.PubMedGoogle Scholar
  9. 9.
    Akashi, M., Loussararian, A. Adelman, D., Saito, M. and Koeffler, H.P. (1990) Lymphotoxin: stimulation and regulation of colony stimulating factors in fibroblasts. J. Cl in. Invest. 85: 121–129.CrossRefGoogle Scholar
  10. 10.
    Koeffler, H.P., Gasson, J. and Tobler, A. (1988) Transcriptional and postranscriptional modulation of myeloid CSF expression by TNF and other agents. Mol. Cell Biol. 8: 3432–3438.PubMedGoogle Scholar
  11. 11.
    Yamato, K., El-Hajjaoui, Z. and Koeffler, H.P. (1989) Regulation of levels of IL-1 mRNA in human fibroblasts. J. Physiol. 139: 610–616.Google Scholar
  12. 12.
    Ross, H. J., Sato, N., Ueyama, Y. and Koeffler, H.P. (1991) Cytokine messenger RNA stability is enhanced in tumor cells. Blood 77: 1787–1795.PubMedGoogle Scholar
  13. 13.
    Dong, G., Chen, Z., Kato, T. and Waes, C.V. (1999) The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. Cancer Res. 59: 3495–3504.PubMedGoogle Scholar
  14. 14.
    Mignati, P. and Rifkin, D.B. (1993) Biology and biochemistry of proteinases in tumor invasion. Physiol. Rev. 73, 161–195.Google Scholar
  15. 15.
    Dano, K., Andreasen, P.A., Grondahl-Hansen, K., Kristensen, P., Nielsen, L.S. and Skriver, L. (1985) Plasminogen activators, tissue degradation and cancer. Adv. Cancer Res. 44, 139–266.PubMedCrossRefGoogle Scholar
  16. 16.
    Behrens, J. (1993) The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res. Treat. 24, 175–184.PubMedCrossRefGoogle Scholar
  17. 17.
    Bernstein, P.L., Herrick, D.J., Prokipcak and Ross, J. (1992) Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev. 6: 642–654.Google Scholar
  18. 18.
    Raymond, V., Atwater, J. A. and Verma, I. M. (1989) Removal of an mRNA destabilizing element correlates with the increased oncogenicity of proto-oncogene fos. Oncogene Res. 4: 861–865.Google Scholar
  19. 19.
    Schiavi, S. C., Wellington, C. L., Shyu, A.-B., Chen, C.Y.A., Greenberg, M.E. and Belasco, J.G. (1994) Multiple elements in the c-fos protein-coding region accelerate mRNA deadenylation and decay by a mechanism coupled to translation. J. Biol. Chem. 269: 3441–3448.PubMedGoogle Scholar
  20. 20.
    Shyu, A-B., Belasco, J.G. and Greenberg, M.E. (1991) Two distinct destabilizing elements in the c-fos message trigger deadenylation as a first step in rapid mRNA decay. Genes Dev. 5: 221–231.PubMedCrossRefGoogle Scholar
  21. 21.
    Wellington, C.L., Greenberg, M.E., and Belasco, J.G. (1993) The destabilizing elements in the codin region of c-fos mRNA are recognized as RNA. Mol. Cell Biol. 13: 5034–5042.PubMedGoogle Scholar
  22. 22.
    Chen, C.Y., You, Y. and Shyu, A. B. (1992) Two cellular proteins bind specifically to a purine-rich sequence necessary for the destabilization function of a c-fos protein coding region determinant of mRNA stability. Mol Cell Biol. 12: 5748–5757.PubMedGoogle Scholar
  23. 23.
    Amara, F.M., Chen, F.Y. and Wright, J. A. (1994) Phorbol ester modulation of a novel cytoplasmic protein binding activity at the 3’-untranslated region of mammalian ribonucleotide reductases R2 mRNA and role in message stability. J. Biol. Chem. 269: 6709–6715.PubMedGoogle Scholar
  24. 24.
    Chen, C.Y., Amara, F.M. and Wright, J. A. (1993) Mammalian ribonucleotide reductase R1 mRNA stability under normal phorbol ester stimulating conditions: involvement of a cis-trans interaction at the 3’untranslated region. EMBO, J. 12: 3977–3986.Google Scholar
  25. 25.
    Chen, C.Y., Amara, F.M. and Wright, J. A. (1994) Defining a novel ribonucleotide reductase R1 mRNA cis element that binds to an unique cytoplasmic trans-acting protein. Nucleic Acid Res. 22: 4796–4797.PubMedCrossRefGoogle Scholar
  26. 26.
    Fan H., Villegas, C., Huang, A. and Wright, J. A. (1996) Suppression of malignancy by the 3’ untranslated regions of ribonucleotide reductase R1 and R2 messenger RNAs Cancer Res. 56: 4366–4369.PubMedGoogle Scholar
  27. 27.
    Shetty, S., Kumar, A. and Idell, S. (1997) Posttranscriptional regulation of urokinase receptor mRNA: identification of a novel urokinase receptor mRNA binding protein in human mesothelioma cells. Mol. Cell. Biol. 17: 1075–1083.PubMedGoogle Scholar
  28. 28.
    Shetty, S. and Idell, S. (1999) Posttranscriptional regulation of urokinase receptor gene expression in lung carcinoma and malignant mesothelioma cells in vitro. Mol. Cell. Biol. 199: 189–200.Google Scholar
  29. 29.
    Brewer, G. (1991) An A+U rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol. Cell. Biol. 11: 2460–2466.Google Scholar
  30. 30.
    Rastinejad, F., Conboy, M.J., Rando, T.A. and Blau, H.M. (1993) Tumor supression by the RNA from the 3’untranslated region of a-tropomyosin. Cell 75:1107–1117.Google Scholar
  31. 31.
    Wang, G.J., Collinge, M., Blasi, F., Pardi, R. and Bender, J.R. (1998) Posttranscriptional regulation of urokinase plasminogen activator receptor messenger RNA levels by leukocyte integrin engagement. Proc. Natl. Acad. Sci. 95: 6296–6301.PubMedCrossRefGoogle Scholar
  32. 32.
    Shetty, S., Kumar, A., Johnson, A.R., Pueblitz, S., Holiday, D., Raghu, G. and Idell, S. (1996) Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs. Am. J. Resp. Cell Mol. Biol. 15: 78–87.Google Scholar
  33. 33.
    Altus, M. S., Pearson, D., Horiuchi, A. and Nagamine, Y. (1987) Inhibition of protein synthesis in LLC-PK1 cells increases calcitonin induced plasminogen activator gene transcription and mRNA stability. Biochem. J. 242: 387–392.PubMedGoogle Scholar
  34. 34.
    Altus, M. S. and Nagamine, Y. (1991) Protein synthesis inhibition stabilizes urokinase-type plasminogen activator mRNA. J. Biol. Chem. 266: 21190–21196.PubMedGoogle Scholar
  35. 35.
    Ziegler, A., Knesel, J., Fabbro, D. and Nagamine, Y. (1991) Protein kinase C down-regulation enhances cAMP-mediated induction of urokinase-type plasminogen activator mRNA in LLC-PK1 cells. J. Biol. Chem. 266: 21067–21074.PubMedGoogle Scholar
  36. 36.
    Ziegler, A., Hagmann, J., Kiefer and Nagamine, Y. (1990) Ca2+ potentiates cAMPdependent expression of urokinase-type plasminogen activator gene through a calmodulin- and protein kinase C-independent mechanism. J. Biol. Chem. 265: 21194–21201.Google Scholar
  37. 37.
    Nanbu, R., Menoud, P.A. and Nagamine, Y. (1994) Multiple instability-regulating sites in the 3’untranslated region of the urokinase-type plasminogen activator mRNA. Mol. Cell. Biol. 14: 4920–4928.PubMedGoogle Scholar
  38. 38.
    Nanbu, R., Montero, L., D’orazio, D. and Nagamine, Y. (1997) Enhanced stability of urokinase-type plasminogen activator mRNA in metastatic breast cancer MDA-MB-231 cells and LLC-PK1 cells down-regulated for protein kinase C-correlation with cytoplasmic heterogeneous nuclear ribonucleoprotein C. Eu. J. Biochem. 247: 169–174.CrossRefGoogle Scholar
  39. 39.
    Henderson, B. R., Tansey, W. P., Phillips, S. M., Ramshaw, I. A. and Kefford, R. F. (1992) Transcriptional and posttranscriptional activation of urokinase plasminogen activator gene expression in metastatic tumor cells. Cancer Res. 52: 2489–2496.PubMedGoogle Scholar
  40. 40.
    Shetty, S. and Idell, S. (2000) Post-transcriptional regulation of urokinase mRNA: identification of a novel urokinase mRNA-binding protein in human lung epithelial cells in vitro. J. Biol. Chem. 275: 13771–13779.CrossRefGoogle Scholar
  41. 41.
    Bosma, P. J. and Kooistra, T. (1991) Different induction of two plasminogen activator inhibitor 1 mRNA species by phorbol ester in human hepatoma cells. J. Biol Chem. 266: 17845–17849.PubMedGoogle Scholar
  42. 42.
    Fattal, P.G., Schneider, D. J., Sobel, B. E. and Billadello, J. J. (1992) Posttranscriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin-like growth factor 1. J. Biol. Chem. 267: 12412–12415.PubMedGoogle Scholar
  43. 43.
    Heaton, J.H., Tillmann-Bogush, M., Leff, N. S. and Gelehrter, T.D. (1998) Cyclic nucleotide regulation of type-1 plasminogen activator-inhibitor mRNA stability in rat hepatoma cells. J. Biol. Chem. 273: 14261–14268.PubMedCrossRefGoogle Scholar
  44. 44.
    Tillmann-Bogush, M., Heaton, J. H. and Gelehrter, T. D. (1999) Cyclic nucleotide regulation of PAI-1 mRNA stability. J. Biol. Chem. 274: 1172–1179.PubMedCrossRefGoogle Scholar
  45. 45.
    Pedersen, H., Brunner, N. Franscis, D., Osterlind, K., Ronne, E., Hansen, H. H., Dano, K. and Grondahl-Hansen, J. (1994) Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 54: 4671–4675.Google Scholar
  46. 46.
    Pedersen, H., Grondahl-Hansen, J., Franscis, D., Osterlind, K., Hansen, H. H., Dano, K. and Brunner, N. (1994) Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res. 54: 120–123.PubMedGoogle Scholar
  47. 47.
    Shetty, S. and Idell, S. (2000) Posttranscriptional regulation of plasminogen activator inhibitor-1 in human lung carcinoma cells in vitro. Am. J. Physiol. 278: 148–156.Google Scholar
  48. 48.
    Maurer, F., Tierney, M. and Medcalf, R. L. (1999) 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. Nu. Acid Res. 27: 1664–1673.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Sreerama Shetty
    • 1
  1. 1.University of Texas Health Center at TylerUSA

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