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Transforming Growth Factor-β

A Key Mediator of Fibrosis

  • Protocol
Fibrosis Research

Part of the book series: Methods in Molecular Medicine ((MIMM,volume 117))

Abstract

Transforming growth factor (TGF)-β is a prototypic multifunctional cytokine whose broad modulatory mechanisms affect numerous biological functions both at the cell and organism levels. These include, but are not limited to, control of immune functions, embryogenesis, carcinogenesis, tissue responses to injury, cell proliferation, extracellular matrix (ECM) synthesis and degradation, and cell migration. The identification of Smad proteins, TGF-β receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, has increased our understanding of the molecular mechanisms underlying TGF-β action. This introductory chapter will outline the current knowledge on how specific signals initiated by the TGF-β receptors are brought to the nucleus to regulate gene expression, with a specific emphasis on how such signaling relates to connective tissue remodeling, repair, and fibrosis.

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References

  1. Roberts, A. B. (1998) Molecular and cell biology of TGF-beta. Miner. Electrolyte Metab. 24(2–3), 111–119.

    Article  PubMed  CAS  Google Scholar 

  2. de Caestecker, M. P., Piek, E., and Roberts, A. B. (2000) Role of transforming growth factor-beta signaling in cancer. J. Natl. Cancer Inst. 92(17), 1388–1402.

    Article  PubMed  Google Scholar 

  3. Chen, W. and Wahl, S. M. (2002) TGF-beta: receptors, signaling pathways and autoimmunity. Curr. Dir. Autoimmun. 5, 62–91.

    Article  PubMed  CAS  Google Scholar 

  4. Varga, J. (2002) Scleroderma and Smads: dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum. 46(7), 1703–1713.

    Article  PubMed  CAS  Google Scholar 

  5. Barcellos-Hoff, M. H. (1996) Latency and activation in the control of TGF-beta. J. Mammary Gland Biol. Neoplasia. 1(4), 353–363.

    Article  Google Scholar 

  6. Attisano, L. and Wrana, J. L. (2002) Signal transduction by the TGF-beta superfamily. Science 296(5573), 1646–1647.

    Article  PubMed  CAS  Google Scholar 

  7. Shi, Y. and Massague, J. (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113(6), 685–700.

    Article  PubMed  CAS  Google Scholar 

  8. Huse, M., Muir, T. W., Xu, L., Chen, Y. G., Kuriyan, J., and Massague, J. (2001) The TGF beta receptor activation process: an inhibitor-to substrate-binding switch. Mol. Cell. 8(3), 671–682.

    Article  PubMed  CAS  Google Scholar 

  9. Di Guglielmo, G. M., LeRoy, C., Goodfellow, A. E., and Wrana, J. L. (2003) Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat. Cell Biol. 5(5), 410–421.

    Article  PubMed  Google Scholar 

  10. Lopez-Casillas, F., Wrana, J. L., and Massagué, J. (1993) Betaglycan presents ligand to the TGF beta signaling receptor. Cell 73(7), 1435–1444.

    Article  PubMed  CAS  Google Scholar 

  11. Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L., and Wrana, J. L. (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95(6), 779–791.

    Article  PubMed  CAS  Google Scholar 

  12. Reguly, T. and Wrana, J. L. (2003) In or out? The dynamics of Smad nucleocytoplasmic shuttling. Trends Cell Biol. 13(5), 216–220.

    Article  PubMed  CAS  Google Scholar 

  13. Fink, S. P., Mikkola, D., Wilson, J. K., and Markowitz, S. (2003) TGF-betainduced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines. Oncogene 22(9), 1317–1323.

    Article  PubMed  CAS  Google Scholar 

  14. Zawel, L., Dai, J. L., Buckhaults, P., et al. (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell. 1(4), 611–617.

    Article  PubMed  CAS  Google Scholar 

  15. Dennler, S., Huet, S., and Gauthier, J. M. (1999) A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. Oncogene 18(8), 1643–1648.

    Article  PubMed  CAS  Google Scholar 

  16. Attisano, L., Silvestri, C., Izzi, L., and Labbe, E. (2001) The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. Mol. Cell Endocrinol. 180(1–2), 3–11.

    Article  PubMed  CAS  Google Scholar 

  17. Miyazono, K. (2000) TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev. 11(1–2), 15–22.

    Article  PubMed  CAS  Google Scholar 

  18. Datta, P. K., Chytil, A., Gorska, A. E., and Moses, H. L. (1998) Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. J. Biol. Chem. 273(52), 34,671–34,674.

    Article  PubMed  CAS  Google Scholar 

  19. Ferrigno, O., Lallemand, F., Verrecchia, F., et al. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-beta/Smad signaling. Oncogene 21(32), 4879–4884.

    Google Scholar 

  20. Janknecht, R., Wells, N. J., and Hunter, T. (1998) TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 12(14), 2114–2119.

    Article  PubMed  CAS  Google Scholar 

  21. Feng, X. H., Zhang, Y., Wu, R. Y., and Derynck, R. (1999) The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev. 12(14), 2153–2163.

    Article  Google Scholar 

  22. Pouponnot, C., Jayaraman, L., and Massagué, J. (1998) Physical and functional interaction of SMADs and p300/CBP. J. Biol. Chem. 273(36), 22,865–22,968.

    Article  PubMed  CAS  Google Scholar 

  23. Shen, X., Hu, P. P., Liberati, N. T., Datto, M. B., Frederick, J. P., and Wang, X. F. (1998) TGF-beta-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein. Mol. Biol. Cell. 9(12), 3309–3319.

    PubMed  CAS  Google Scholar 

  24. Topper, J. N., Dichiara, M. R., Brown, J. D., et al. (1998) CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor beta transcriptional responses in endothelial cells. Proc. Natl. Acad. Sci. USA 95(16), 9506–9511.

    Article  PubMed  CAS  Google Scholar 

  25. Verrecchia, F., Pessah, M., Afti, A., and Mauviel, A. (2000) Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation. J. Biol. Chem. 275(39), 30,226–30,231.

    Article  PubMed  CAS  Google Scholar 

  26. Ghosh, A. K., Yuan, W., Mori, Y., Chen, S. J., and Varga, J. (2001) Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J. Biol. Chem. 276(14), 11,041–11,048.

    Article  PubMed  CAS  Google Scholar 

  27. Schiller, M., Verrecchia, F., and Mauviel, A. (2003) Cyclic adenosine 3′,5′-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. Oncogene 22(55), 8881–8890.

    Article  PubMed  CAS  Google Scholar 

  28. Wotton, D., Lo, R. A., Lee, S., and Massague, J. (1999) A Smad transcriptional corepressor. Cell 97(1), 29–39.

    Article  PubMed  CAS  Google Scholar 

  29. Luo, K., Stroschein, S. L., Wang, W., et al. (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev. 13(17), 2196–2206.

    Article  PubMed  CAS  Google Scholar 

  30. Sun, Y., Liu, X., Ng-Eaton, E., Lodish, H. F., and Weinberg, R. A. (1999) SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc. Natl. Acad. Sci. USA 96(22), 12,442–12,447.

    Article  PubMed  CAS  Google Scholar 

  31. Kim, R. H., Wang, D., Tsang, M., et al. (2000) A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev. 14(13), 1605–1616.

    PubMed  CAS  Google Scholar 

  32. Verrecchia, F. and Mauviel, A. (2002) Control of connective tissue gene expression by TGF beta: role of Smad proteins in fibrosis. Curr. Rheumatol. Rep. 4(2), 143–149.

    Article  PubMed  Google Scholar 

  33. O’Kane, S. and Ferguson, M. W. (1997) Transforming growth factor beta s and wound healing. Int. J. Biochem. Cell Biol. 29(1), 63–78.

    Article  CAS  Google Scholar 

  34. Bitzer, M., von Gersdorff, G., Liang, D., et al. (2000) A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes Dev. 14(2), 187–197.

    PubMed  CAS  Google Scholar 

  35. Verrecchia, F., Tacheau, C., Wagner, E. G., and Mauviel, A. (2003) A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression. J. Biol. Chem. 278(3), 1585–1593.

    Article  PubMed  CAS  Google Scholar 

  36. Verrecchia, F., Wagner, E. F., and Mauviel, A. (2002) Distinct involvement of the Jun-N-terminal kinase and NF-κB pathways in the repression of the human COL1A2 gene by TNF-α. EMBO Rep. 3(11), 1069–1074.

    Article  PubMed  CAS  Google Scholar 

  37. Han, Z., Boyle, D. L., Chang, L., et al. (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest. 108(1), 73–81.

    PubMed  CAS  Google Scholar 

  38. Ulloa, L., Doody, J., and Massagué, J. (1999) Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397(6721), 710–713.

    Article  PubMed  CAS  Google Scholar 

  39. Higashi, K., Kouba, D. J., Song, Y. J., Uitto, J., and Mauviel, A. (1998) A proximal element within the human alpha 2(I) collagen (COL1A2) promoter, distinct from the tumor necrosis factor-alpha response element, mediates transcriptional repression by interferon-gamma. Matrix Biol. 16(8), 447–456.

    Article  PubMed  CAS  Google Scholar 

  40. Higashi, K., Inagaki, Y., Fujimori, K., Nakao, A., Kaneko, H., and Nakatsuka, I. (2003) Interferon-gamma interferes with transforming growth factor-beta signaling through direct interaction of YB-1 with Smad3. J. Biol. Chem. 278(44), 43,470–43,479.

    Article  PubMed  CAS  Google Scholar 

  41. Ashcroft, G. S., Yang, X., Glick, A. B., et al. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat. Cell Biol. 1(5), 260–266.

    Article  PubMed  CAS  Google Scholar 

  42. Flanders, K. C., Sullivan, C. D., Fujii, M., et al. (2002) Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am. J. Pathol. 160(3), 1057–1068.

    Article  PubMed  CAS  Google Scholar 

  43. Sato, M., Muragaki, Y., Saika, S., Roberts, A. B., and Ooshmia, A. (2003) Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest. 112(10), 1486–1494.

    PubMed  CAS  Google Scholar 

  44. Wang, B., Hao, J., Jones, S. C., Yee, M. S., Roth, J. C., and Dixon, I. M. (2002) Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am. J. Physiol. Heart Circ. Physiol. 282(5), H1685–1696.

    PubMed  CAS  Google Scholar 

  45. Wang, H., Yang, G. H., Bu, H., Zhou, Q., Gui, L. X., Wang, S. L., and Ye, L. (2003) Systematic analysis of the TGF-beta/Smad signalling pathway in the Rhabdomyosarcoma cell line RD. Int. J. Exp. Pathol. 84(3), 153–163.

    Article  PubMed  CAS  Google Scholar 

  46. Mori, Y., Chen, S. J., and Varga, J. (2003) Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Arthritis Rheum. 48(7), 1964–1978.

    Article  PubMed  CAS  Google Scholar 

  47. Nakao, A., Fujii, M., Matsumura, R., et al. (1999) Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J. Clin. Invest. 104(1), 5–11.

    Article  PubMed  CAS  Google Scholar 

  48. Lan, H. Y., Mu, W., Tomita, N., et al. (2003) Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J. Am. Soc. Nephrol. 14(6), 1535–1548.

    Article  PubMed  CAS  Google Scholar 

  49. Dooley, S., Hamzavi, J., Breitkopf, K., et al. (2003) Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125(1), 178–191.

    Article  PubMed  CAS  Google Scholar 

  50. Laping, N. J., Grygielko, E., Mathur, A., et al. (2002) Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol. Pharmacol. 62(10), 58–64.

    Article  PubMed  CAS  Google Scholar 

  51. Grygeiklo, E. T., Martin, W. M., Tweed, C. W., et al. (2005) Inhibition of gene markers of fibrosis with a novel inhibitor of TGFta-type I receptor kinase in puromycin-induced nephritis. J. Pharmacol. Exp. Ther. [Epub ahead of print].

    Google Scholar 

  52. Bonniaud, P., Margetts, P. J., Kolb, M., et al. (2005) Progressive transforming growth factor {beta}1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am. J. Resp. Crit. Care Med. 171(8), 889–898.

    Article  PubMed  Google Scholar 

  53. de Gouville, A. C., Boullay, V., Krysa, G., et al. (2005) Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br. J. Pharmacol. [Epub ahead of print].

    Google Scholar 

  54. Yang, Y. A., Dukhanina, O., Tang, B., et al. (2002) Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109(12), 1607–1615.

    PubMed  CAS  Google Scholar 

  55. He, W., Li, A. G., Wang, D., et al. (2002) Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues. EMBO J. 21(11), 2580–2590.

    Article  PubMed  CAS  Google Scholar 

  56. Denton, C. P., Zheng, B., Evans, L. A., et al. (2003) Fibroblast-specific expression of a kinase-deficient type II transforming growth factor beta (TGFbeta) receptor leads to paradoxical activation of TGFbeta signaling pathways with fibrosis in transgenic mice. J. Biol. Chem. 278(27), 25,109–25,119.

    Article  PubMed  CAS  Google Scholar 

  57. Javelaud, D. and Mauviel, A. (2004) Mammalian transforming growth factorbetas: Smad signaling and physio-pathological roles. Int. J. Biochem. Cell Biol. 36, 1161–1165.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. INSERM U697, Hopital Saint-Louis, Paris, France

    Alain Mauviel

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  1. Alain Mauviel
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Editors and Affiliations

  1. Feinberg School of Medicine, Northwestern University, Chicago, IL

    John Varga MD

  2. College of Physicians and Surgeons, Columbia University, New York, NY

    David A. Brenner MD

  3. University of Michigan Medical School, Ann Arbor, MI

    Sem H. Phan MD, PhD

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© 2005 Humana Press Inc.

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Mauviel, A. (2005). Transforming Growth Factor-β. In: Varga, J., Brenner, D.A., Phan, S.H. (eds) Fibrosis Research. Methods in Molecular Medicine, vol 117. Humana Press. https://doi.org/10.1385/1-59259-940-0:069

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  • DOI: https://doi.org/10.1385/1-59259-940-0:069

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-479-1

  • Online ISBN: 978-1-59259-940-0

  • eBook Packages: Springer Protocols

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