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:

Annexin V inhibits the 12-O-tetradecanoylphorbol-13-acetate-induced activation of Ras/extracellular signal-regulated kinase (ERK) signaling pathway upstream of Shc in MCF-7 cells

Oncogene volume 19, pages 2904–2912 (2000)Cite this article

Abstract

Annexin V is a Ca2+-dependent phospholipid binding protein. Although it has been shown to inhibit protein kinase C (PKC) in cell-free systems, its role in the intact cell is unclear. A stable MCF-7 human breast cancer cell overexpression system was established to investigate the function of annexin V. In these cells, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation and kinase activity of ERK1/2 were suppressed. Morphological changes induced by TPA were reduced by annexin V overexpression as well as by the pan-PKC inhibitor, bisindolylmaleimide I, and by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor, PD98059. TPA-induced MEK1/2 and Raf-1 phosphorylation were reduced in these cells. The TPA-enhanced active Ras, and its association with Raf-1, were reduced. TPA treatment of MCF-7 cells caused an increased association of Shc with Grb2. However, this increased association was prevented in the annexin V-overexpressors. p21WAF/CIP1 is responsible for inhibition of cell cycle progression in MCF-7 cells. TPA induced the expression of p21WAF/CIP1 to a greater extent in MCF-7 parent and control plasmid cells than in annexin V overexpressors. PD98059 inhibited this increase, suggesting that TPA upregulation of p21WAF/CIP1 occurs via the MEK pathway, and that annexin V overexpression blunts it. This work shows that annexin V overexpression suppresses the TPA-induced Ras/ERK signaling by inhibiting at/or upstream of Shc, possibly through the inhibition of PKCs.

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
Figure 8
Figure 9

Similar content being viewed by others

References

  • Abe M and Kufe D . 1986 J Cell Physiol 126: 126–132

  • Alblas J, Slager-Davidov R, Steenbergh PH, Sussenbach JS and van der Burg B . 1998 Oncogene 16: 131–139

  • Arita Y, O'Driscoll KR and Weinstein IB . 1994 Int J Cancer 56: 229–235

  • Bruder JT, Heidecker G and Rapp UR . 1992 Genes Dev 6: 545–556

  • Buckland AG and Wilton DC . 1998 Biochim Biophys Acta 1391: 367–376

  • Buday L and Downward J . 1993 Cell 73: 611–620

  • Cobb MH and Goldsmith EJ . 1995 J Biol Chem 270: 14843–14846

  • Comera C, Rothhut B, Cavadore JC, Vilgrain I, Cochet C, Chambaz E and Russo-Marie F . 1989 J Cell Biochem 40: 361–370

  • Dekker LV and Parker PJ . 1994 Trends Biochem Sci 19: 73–77

  • Devente JE, Kukoly CA, Bryant WO, Posekany KJ, Chen JM, Fletcher DJ, Parker PJ, Pettit GJ, Lozano G, Cook PP and Ways DK . 1995 J Clin Invest 96: 1874–1886

  • Dickson B and Hafen E . 1994 Curr Opin Genet Dev 4: 64–70

  • Dubois T, Oudinet JP, Mira JP and Russo-Marie F . 1996 Biochim Biophys Acta 1313: 290–294

  • Dubois T, Mira JP, Feliers D, Solito E, Russo-Marie F and Oudinet JP . 1998 Biochem J 330: 1277–1282

  • Dufourny B, Alblas J, van Teeffelen HA, van Schaik FM, van der Burg B, Steenbergh PH and Sussenbach JS . 1997 J Biol Chem 272: 31163–31171

  • El-Shemerly MY, Besser D, Nagasawa M and Nagamine Y . 1997 J BiolChem 272: 30599–30602

  • Fabian JR, Daar IO and Morrison DK . 1993 Mol Cell Biol 13: 7170–7179

  • Finney RE, Robbins SM and Bishop JM . 1993 Curr Biol 3: 805–812

  • Hallberg B, Rayter SI and Downward J . 1994 J Biol Chem 269: 3913–3916

  • Herschman HR, Lim RW, Brankow DW and Fujiki H . 1989 Carcinogenesis 10: 1495–1498

  • Kaplan R, Jaye M, Burgess WH, Schlaepfer DD and Haigler HT . 1988 J Biol Chem 263: 8037–8043

  • Karube A, Shidara Y, Hayasaka K, Maki M and Tanaka T . 1995 Gynecol Oncol 58: 295–300

  • Kato S, Ben TL and De Luca LM . 1988 Exp Cell Res 179: 31–41

  • Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D and Rapp UR . 1993 Nature 364: 249–252

  • Leevers SJ, Paterson HF and Marshall CJ . 1994 Nature 369: 411–414

  • Marshall CJ . 1994 Curr Opin Genet Dev 4: 82–89

  • Meloche S, Seuwen K, Pages G and Pouyssegur J . 1992 Mol Endocrinol 6: 845–854

  • Menapace L, Armato U and Whitfield JF . 1987 Biochem Biophys Res Commun 148: 1295–1303

  • Newton AC . 1995 J Biol Chem 270: 28495–28498

  • Nishizuka Y . 1995 FASEB J 9: 484–496

  • Nori M, L'Allemain G and Weber MJ . 1992 Mol Cell Biol 12: 936–945

  • Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S and Pouyssegur J . 1993 Proc Natl Acad Sci USA 90: 8319–8323

  • Raynal P, Hullin F, Ragab-Thomas JM, Fauvel J and Chap H . 1993 Biochem J 292: 759–765

  • Raynal P, Kuijpers G, Rojas E and Pollard HB . 1996 FEBS Lett 392: 263–268

  • Raynal P and Pollard HB . 1994 Biochim Biophys Acta 1197: 63–93

  • Rothhut B, Dubois T, Feliers D, Russo-Marie F and Oudinet JP . 1995 Eur J Biochem 232: 865–872

  • Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J and Pelicci PG . 1992 Nature 360: 689–692

  • Schlaepfer DD, Jones J and Haigler HT . 1992 Biochemistry 31: 1886–1891

  • Schlaepfer DD and Haigler HT . 1990 J Cell Biol 111: 229–238

  • Shibata S, Sato H and Maki M . 1992a Tohoku J Exp Med 166: 479–481

  • Shibata S, Sato H and Maki M . 1992b J Biochem Tokyo 112: 552–556

  • Shibata S, Sato H, Ota H, Karube A, Takahashi O and Tanaka T . 1997 Gynecol Oncol 66: 217–221

  • Sozeri O, Vollmer K, Liyanage M, Frith D, Kour G, Mark GE III, and Stabel S . 1992 Oncogene 7: 2259–2262

  • Theobald J, Smith PD, Jacob SM and Moss SE . 1994 Biochim Biophys Acta 1223: 383–390

  • Theobald J, Hanby A, Patel K and Moss SE . 1995 Br J Cancer 71: 786–788

  • Thomas SM, DeMarco M, D'Arcangelo G, Halegoua S and Brugge JS . 1992 Cell 68: 1031–1040

  • Troppmair J, Bruder JT, Munoz H, Lloyd PA, Kyriakis J, Banerjee P, Avruch J and Rapp UR . 1994 J Biol Chem 269: 7030–7035

  • Utsumi T . 1992 Nippon Sanka Fujinka Gakkai Zasshi 44: 793–799

  • Valette A, Gas N, Jozan S, Roubinet F, Dupont MA and Bayard F . 1987 Cancer Res 47: 1615–1620

  • Van Aelst L, Barr M, Marcus S, Polverino A and Wigler M . 1993 Proc Natl Acad Sci USA 90: 6213–6217

  • van der Geer P and Pawson T . 1995 Trends Biochem Sci 20: 277–280

  • Vojtek AB, Hollenberg SM and Cooper JA . 1993 Cell 74: 205–214

  • Warne PH, Viciana PR and Downward J . 1993 Nature 364: 352–355

  • Waskiewicz AJ and Cooper JA . 1995 Curr Opin Cell Biol, 7: 798–805

  • Winkelstein A, Simon PL, Myers PA and Weaver LD . 1986 Exp Hematol 14: 1023–1028

  • Younus J and Gilchrest BA . 1992 J Cell Physiol 152: 232–239

  • Zhang XF, Settleman J, Kyriakis JM, Takeuchi-Suzuki E, Elledge SJ, Marshall MS, Bruder JT, Rapp UR and Avruch J . 1993 Nature 364: 308–313

Download references

Acknowledgements

We would like to thank Drs Douglas R Lowy and Wayne Anderson, National Cancer Institute, Bethesda, MD, for reading the manuscript and giving useful suggestions.

Author information

Authors and Affiliations

  1. Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institute of Health, Bethesda, 20892-4255, Maryland, MD, USA

    Hirokazu Sato, Hideaki Ogata & Luigi M De Luca

Authors
  1. Hirokazu Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideaki Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luigi M De Luca
    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

Sato, H., Ogata, H. & De Luca, L. Annexin V inhibits the 12-O-tetradecanoylphorbol-13-acetate-induced activation of Ras/extracellular signal-regulated kinase (ERK) signaling pathway upstream of Shc in MCF-7 cells. Oncogene 19, 2904–2912 (2000). https://doi.org/10.1038/sj.onc.1203615

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203615

Keywords

This article is cited by

Search

Advanced search

Quick links