Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The second loop of occludin is required for suppression of Raf1-induced tumor growth

Oncogene volume 24, pages 4412–4420 (2005)Cite this article

Abstract

Tight junctions (TJs) regulate epithelial cell polarity and paracellular permeability. Loss of functional TJs is commonly associated with epithelial cell-derived cancers. Raf1-mediated transformation of rat salivary gland epithelial cells (Pa4-Raf1) induces transcriptional downregulation of the TJ protein occludin and forced re-expression of occludin rescues polarized phenotype of epithelial cells. In the present study, we used this model to examine how specific structural modifications in the occludin protein affect its function in vitro and influence tumor growth in vivo. Our results revealed that neither the C-terminal nor the N-terminal half of occludin alone were sufficient to rescue cells from transformation by Raf1. However, forced expression of an occludin mutant lacking the first extracellular loop was sufficient to rescue cells from Raf1-mediated transformation. Interestingly, forced expression of an occludin mutant lacking the second extracellular loop did not rescue the epithelial phenotype in vitro nor did it prevent tumor growth in vivo. These results demonstrate that the TJ protein occludin has a potent inhibitory effect on the Raf1-mediated tumorigenesis and the second extracellular loop of occludin appears to be critical for this function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ando-Akatsuka Y, Saitou M, Hirase T, Kishi M, Sakakibara A, Itoh M, Yonemura S, Furuse M and Tsukita S . (1996). J. Cell Biol., 133, 43–47.

  • Balda MS, Whitney JA, Flores C, Gonzalez S, Cereijido M and Matter K . (1996). J. Cell Biol., 134, 1031–1049.

  • Bamforth SD, Kniesel U, Wolburg H, Engelhardt B and Risau W . (1999). J. Cell Sci., 112, 1879–1888.

  • Chen Y, Merzdorf C, Paul DL and Goodenough DA . (1997). J. Cell Biol., 138, 891–899.

  • Cobb MH, Hepler JE, Cheng M and Robbins D . (1994). Semin. Cancer Biol., 5, 261–268.

  • de Vries JE, ten Kate J and Bosman FT . (1996). Pathol. Res. Pract., 192, 658–668.

  • Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S and Tsukita S . (1993). J. Cell Biol., 123, 1777–1788.

  • Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S and Tsukita S . (1994). J. Cell Biol., 127, 1617–1626.

  • Furuse M, Sasaki H, Fujimoto K and Tsukita S . (1998). J. Cell Biol., 143, 391–401.

  • Gonzalez-Mariscal L, Betanzos A, Nava P and Jaramillo BE . (2003). Prog. Biophys. Mol. Biol., 81, 1–44.

  • Hoover KB, Liao SY and Bryant PJ . (1998). Am. J. Pathol., 153, 1767–1773.

  • Hopkins AM, Walsh SV, Verkade P, Boquet P and Nusrat A . (2003). J. Cell Sci., 116, 725–742.

  • Kimura Y, Shiozaki H, Hirao M, Maeno Y, Doki Y, Inoue M, Monden T, Ando-Akatsuka Y, Furuse M, Tsukita S and Monden M . (1997). Am. J. Pathol., 151, 45–54.

  • Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP and Sukumar S . (2003). Oncogene, 22, 2021–2033.

  • Lacaz-Vieira F, Jaeger MM, Farshori P and Kachar B . (1999). J. Membr. Biol., 168, 289–297.

  • Lan M, Kojima T, Osanai M, Chiba H and Sawada N . (2004). Carcinogenesis, 25, 2385–2395.

  • Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H and Downward J . (2000). Genes Dev., 14, 2610–2622.

  • Li D and Mrsny RJ . (2000). J. Cell. Biol., 148, 791–800.

  • Li D, Lin HH, McMahon M, Ma H and Ann DK . (1997). J. Biol. Chem., 272, 25062–25070.

  • Matter K and Balda MS . (1998). J. Cell Sci., 111, 511–519.

  • Matter K and Balda MS . (2003). Nat. Rev. Mol. Cell Biol., 4, 225–236.

  • McCarthy KM, Skare IB, Stankewich MC, Furuse M, Tsukita S, Rogers RA, Lynch RD and Schneeberger EE . (1996). J. Cell Sci., 109, 2287–2298.

  • Medina R, Rahner C, Mitic LL, Anderson JM and Van Itallie CM . (2000). J. Membr. Biol., 178, 235–247.

  • Michl P, Barth C, Buchholz M, Lerch MM, Rolke M, Holzmann KH, Menke A, Fensterer H, Giehl K, Lohr M, Leder G, Iwamura T, Adler G and Gress TM . (2003). Cancer Res., 63, 6265–6271.

  • Mitic LL, Schneeberger EE, Fanning AS and Anderson JM . (1999). J. Cell Biol., 146, 683–693.

  • Morrison DK and Cutler RE . (1997). Curr. Opin. Cell Biol., 9, 174–179.

  • Nakamura T, Blechman J, Tada S, Rozovskaia T, Itoyama T, Bullrich F, Mazo A, Croce CM, Geiger B and Canaani E . (2000). Proc. Natl. Acad. Sci. USA, 97, 7284–7289.

  • Nottage M and Siu LL . (2002). Curr. Pharm. Des., 8, 2231–2242.

  • Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y and Tsukita S . (1997). J. Cell Biol., 137, 1393–1401.

  • Sanders SE, Madara JL, McGuirk DK, Gelman DS and Colgan SP . (1995). Epithelial. Cell Biol., 4, 25–34.

  • Tobioka H, Isomura H, Kokai Y, Tokunaga Y, Yamaguchi J and Sawada N . (2004). Hum. Pathol., 35, 159–164.

  • Tsukita S, Furuse M and Itoh M . (2001). Nat. Rev. Mol. Cell Biol., 2, 285–293.

  • Van Itallie CM and Anderson JM . (1997). J. Cell Sci., 110, 1113–1121.

  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM and Bos JL . (1988). N. Engl. J. Med., 319, 525–532.

  • Wong V and Gumbiner BM . (1997). J. Cell Biol., 136, 399–409.

Download references

Acknowledgements

We thank GT Brown and M Utech for help in manuscript preparation, A Akyildiz for technical assistance and D Hunt for both. NIH Grants DK 59888, DK64399, DK61379, DK72564 and the Crohn's and Colitis Foundation of America supported this work.

Author information

Authors and Affiliations

  1. Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, 615 Michael Street, Atlanta, GA, 30322, USA

    Zili Wang, Kenneth J Mandell, Charles A Parkos & Asma Nusrat

  2. Unity Pharmaceuticals, 11620 Buena Vista Dr., Los Altos Hills, CA, 94022, USA

    Randall J Mrsny

Authors
  1. Zili Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth J Mandell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles A Parkos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Randall J Mrsny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asma Nusrat
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Z., Mandell, K., Parkos, C. et al. The second loop of occludin is required for suppression of Raf1-induced tumor growth. Oncogene 24, 4412–4420 (2005). https://doi.org/10.1038/sj.onc.1208634

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208634

Keywords

This article is cited by

Search

Advanced search

Quick links