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:

Mutant α-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma

Oncogene volume 23, pages 2630–2639 (2004)Cite this article

Abstract

The precise role of α-actinin-4 encoding gene (ACTN4) is not very well understood. It has been reported to elicit tumor suppressor activity and to regulate cellular motility. To further assess the function of human ACTN4, we studied a lung carcinoma cell line expressing a mutated α-actinin-4, which is recognized as a tumor antigen by autologous CD8+ cytotoxic T lymphocytes (CTL). Confocal immunofluorescence microscopy indicated that, while wild-type (WT) α-actinin-4 stains into actin cytoskeleton and cell surface ruffles, the mutated protein is only dispersed in the cytoplasm of the lung carcinoma cells. This loss of association with the cell surface did not appear to correlate with a decrease in in vitro α-actinin-4 crosslinking to filamentous (F)-actin. Interestingly, experiments using cell lines stably expressing ACTN4 demonstrated that as opposed to WT gene, mutant ACTN4 was unable to inhibit tumor cell growth in vitro and in vivo. Moreover, the expression of mutant α-actinin-4 resulted in the loss of tumor cell capacity to migrate. The identification of an inactivating mutation in ACTN4 emphasizes its role as a tumor suppressor gene and underlines the involvement of cytoskeleton alteration in tumor development and metastasis.

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

Similar content being viewed by others

Abbreviations

CTL:

cytotoxic T lymphocytes

WT:

wild-type

Mut:

mutant

F-actin:

filamentous-actin

mAb:

monoclonal antibodies

ECM:

extracellular matrix

References

  • Akamatsu H, Ichihara-Tanaka K, Ozono K, Kamiike W, Matsuda H and Sekiguchi K . (1996). Cancer Res., 56, 4541–4546.

  • Araki N, Hatae T, Yamada T and Hirohashi S . (2000). J. Cell. Sci., 113 (Part 18), 3329–3340.

  • Asselin-Paturel C, Echchakir H, Carayol G, Gay F, Opolon P, Grunenwald D, Chouaib S and Mami-Chouaib F . (1998). Int. J. Cancer, 77, 7–12.

  • Beck-Engeser GB, Monach PA, Mumberg D, Yang F, Wanderling S, Schreiber K, Espinosa III R, Le Beau MM, Meredith SC and Schreiber H . (2001). J. Exp. Med., 194, 285–300.

  • Beggs AH, Byers TJ, Knoll JH, Boyce FM, Bruns GA and Kunkel LM . (1992). J. Biol. Chem., 267, 9281–9288.

  • Ben-Ze'ev A . (1997). Curr. Opin. Cell Biol., 9, 99–108.

  • Ben-Ze'ev A, Rodriguez Fernandez JL, Gluck U, Salomon D and Geiger B . (1994). Adv. Exp. Med. Biol., 358, 147–157.

  • Boyd J, Risinger JI, Wiseman RW, Merrick BA, Selkirk JK and Barrett JC . (1995). Proc. Natl. Acad. Sci. USA, 92, 11534–11538.

  • Bullions LC, Notterman DA, Chung LS and Levine AJ . (1997). Mol. Cell. Biol., 17, 4501–4508.

  • Burridge K, Nuckolls G, Otey C, Pavalko F, Simon K and Turner C . (1990). Cell Differ. Dev., 32, 337–342.

  • Carpen O, Pallai P, Staunton DE and Springer TA . (1992). J. Cell Biol., 118, 1223–1234.

  • Davison MD and Critchley DR . (1988). Cell, 52, 159–160.

  • Djinovic-Carugo K, Young P, Gautel M and Saraste M . (1999). Cell, 98, 537–546.

  • Dorothee G, Vergnon I, Menez J, Echchakir H, Grunenwald D, Kubin M, Chouaib S and Mami-Chouaib F . (2002). J. Immunol., 169, 809–817.

  • Echchakir H, Dorothee G, Vergnon I, Menez J, Chouaib S and Mami-Chouaib F . (2002). Proc. Natl. Acad. Sci. USA, 99, 9358–9363.

  • Echchakir H, Mami-Chouaib F, Vergnon I, Baurain JF, Karanikas V, Chouaib S and Coulie PG . (2001). Cancer Res., 61, 4078–4083.

  • Friedl P and Wolf K . (2003). Nat. Rev. Cancer, 3, 362–374.

  • Fujimori T and Takeichi M . (1993). Mol. Biol. Cell, 4, 37–47.

  • Geiger B, Ayalon O, Ginsberg D, Volberg T, Rodriguez Fernandez JL, Yarden Y and Ben-Ze'ev A . (1992). Cold Spring Harbor Symp. Quant. Biol., 57, 631–642.

  • Gimona M, Kazzaz JA and Helfman DM . (1996). Proc. Natl. Acad. Sci. USA, 93, 9618–9623.

  • Gluck U and Ben-Ze'ev A . (1994). J. Cell Sci., 107 (Part 7), 1773–1782.

  • Gluck U, Kwiatkowski DJ and Ben-Ze'ev A . (1993). Proc. Natl. Acad. Sci. USA, 90, 383–387.

  • Gonzalez AM, Otey C, Edlund M and Jones JC . (2001). J. Cell Sci., 114, 4197–4206.

  • Haber D and Harlow E . (1997). Nat. Genet., 16, 320–322.

  • Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, Yamada Y, Chiba H and Hirohashi S . (1998). J. Cell Biol., 140, 1383–1393.

  • Horwitz A, Duggan K, Buck C, Beckerle MC and Burridge K . (1986). Nature, 320, 531–533.

  • Hynes RO . (1992). Curr. Opin. Genet. Dev., 2, 621–624.

  • Janmey PA and Chaponnier C . (1995). Curr. Opin. Cell Biol., 7, 111–117.

  • Jiang WG . (1995). Eur. J. Surg. Oncol., 21, 307–309.

  • Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH and Pollak MR . (2000). Nat. Genet., 24, 251–256.

  • Knudsen KA, Soler AP, Johnson KR and Wheelock MJ . (1995). J. Cell Biol., 130, 67–77.

  • Kos CH, Le TC, Sinha S, Henderson JM, Kim SH, Sugimoto H, Kalluri R, Gerszten RE and Pollak MR . (2003). J. Clin. Invest., 111, 1683–1690.

  • Millake DB, Blanchard AD, Patel B and Critchley DR . (1989). Nucleic Acids Res., 17, 6725.

  • Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK and Yamada KM . (1995). J. Cell Biol., 131, 791–805.

  • Nikolopoulos SN, Spengler BA, Kisselbach K, Evans AE, Biedler JL and Ross RA . (2000). Oncogene, 19, 380–386.

  • Otey CA, Pavalko FM and Burridge K . (1990). J. Cell Biol., 111, 721–729.

  • Otey CA, Vasquez GB, Burridge K and Erickson BW . (1993). J. Biol. Chem., 268, 21193–21197.

  • Prasad GL, Fuldner RA and Cooper HL . (1993). Proc. Natl. Acad. Sci. USA, 90, 7039–7043.

  • Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E and Rosenberg SA . (1996). J. Exp. Med., 183, 1185–1192.

  • Rodriguez Fernandez JL, Geiger B, Salomon D, Sabanay I, Zoller M and Ben-Ze'ev A . (1992). J. Cell Biol., 119, 427–438.

  • Spengler BA, Lazarova DL, Ross RA and Biedler JL . (1997). Oncol. Res., 9, 467–476.

  • Tsukita S, Itoh M, Nagafuchi A and Yonemura S . (1993). J. Cell Biol., 123, 1049–1053.

  • Vleminckx K, Vakaet Jr L, Mareel M, Fiers W and van Roy F . (1991). Cell, 66, 107–119.

  • Wachsstock DH, Wilkins JA and Lin S . (1987). Biochem. Biophys. Res. Commun., 146, 554–560.

  • Wang HY, Zhou J, Zhu K, Riker AI, Marincola FM and Wang RF . (2002). J. Exp. Med., 195, 1397–1406.

  • Zutter MM, Santoro SA, Staatz WD and Tsung YL . (1995). Proc. Natl. Acad. Sci. USA, 92, 7411–7415.

Download references

Acknowledgements

We thank Dr P Coulie for helpful discussions. We also thank Dr A Bensussan for critically reading the manuscript and Pr D Bellet and JP Le Vilain for rabbit polyclonal Ab production. We also thank Drs J Bernard and P Hollender for their help with cell migration assay and Dr D Grunenwald from the thoracic surgery department of the Institut Mutualiste Montsouris, Paris, France. We also acknowledge Dr P Opolon for her help with cell visualization, D Challuau for technical assistance in in vivo experiments and P Ardouin and all the staff from the IGR Animal Facility for animal care assistance. This work was supported by grants from the Institut Gustave Roussy (IGR), Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche sur le Cancer (ARC), The Fondation de France, Comité tumeurs solides. JM was supported by a fellowship from the IGR. BLMC and GD contributed equally to this work.

Author information

Authors and Affiliations

  1. Laboratoire Cytokines et Immunologie des tumeurs Humaines, U487 INSERM, Institut Fédératif de Recherche 54, Institut Gustave Roussy, Villejuif Cedex, F-94805, France

    Jeanne Menez, Béatrice Le Maux Chansac, Guillaume Dorothée, Isabelle Vergnon, Abdelali Jalil, Salem Chouaib & Fathia Mami-Chouaib

  2. Dynamique du Cytosquelette, Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Gif-sur-Yvette, 91198, France

    Marie-France Carlier

Authors
  1. Jeanne Menez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Béatrice Le Maux Chansac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guillaume Dorothée
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Isabelle Vergnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdelali Jalil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marie-France Carlier
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salem Chouaib
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fathia Mami-Chouaib
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fathia Mami-Chouaib.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Menez, J., Chansac, B., Dorothée, G. et al. Mutant α-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma. Oncogene 23, 2630–2639 (2004). https://doi.org/10.1038/sj.onc.1207347

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207347

Keywords

This article is cited by

Search

Advanced search

Quick links