Role of Na+/H+-Antiporter in Growth Stimulation by Ha-ras

  • Hans Grunicke
  • Karl Maly
  • Hermann Oberhuber
  • Wolfgang Doppler
  • Johann Hoflacher
  • Boris W. Hochleitner
  • Rolf Jaggi
  • Bernd Groner
Part of the NATO ASI Series book series (NSSA, volume 7)


Expression of the transforming Ha-ras oncogene in MMTV-LTR-Ha-ras transfected 3T3 fibroblasts causes a growth factor independent intracellular alkalinization by a dimethylamiloride sensitive mechanism. The phenomenon is accompanied by a desensitization of the intracellular calcium mobilizing system to serum growth factors and an increase in the generation of inositol phosphates. Data are presented which support the assumption that the mobilization of intracellular Ca2+ occurs by a Na+-dependent mechanism. The results are discussed as indicating a constitutive activation of growth factor signal transduction by transforming Ha-ras. The exact sequences of events initiated by the oncogene, however, remains to be elucidated.


Inositol Phosphate Oncogene Expression Calcium Free Medium Intracellular Alkalinization Serum Growth Factor 
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  1. 1.
    T. R. Hesketh, J. P. Moore, J. D. H. Morris, M. V. Taylor, J. Rogers, T. A. Smith, and J. C. Metcalfe, A common sequence of calcium and pH signals in the mytogenic stimulation of eukaryotic cells, Nature 313: 481 (1985).PubMedCrossRefGoogle Scholar
  2. 2.
    W. H. Moolenaar, Effects of growth factors on cytoplasmic pH regulation, Ann.Rev.Physiol. 48: 363 (1986).CrossRefGoogle Scholar
  3. 3.
    R. A. Lagarde, and J. M. Pouyssegur, The Na+/H+-antiport in cancer, Cancer Biochem.Biophys. 9: 1 (1986).PubMedGoogle Scholar
  4. 4.
    R. Jaggi, B. Salmons, D. Muellener, and B. Groner, The v-mos and H-ras oncogene expression represses glucocorticoid hormone dependent transcription from the mouse mammary tumor virus LTR, EMBO J. 5: 2609 (1986).PubMedGoogle Scholar
  5. 5.
    W. Doppler, R. Jaggi, and B. Groner, Induction of v-mos and activated Ha-ras oncogene expression in quiescent NIH 3T3 cells causes intracellular alkalinization and cell-cycle progression, Gene 54: 145 (1987)CrossRefGoogle Scholar
  6. 6.
    K. Maly, H. Oberhuber, W. Doppler, J. Hoflacher, R. Jaggi, B. Groner, and H. Grunicke, Effect of Ha-ras on phosphatidylinositol metabolism Na+/H+-antiporter and mobilization of intracellular calcium, Adv.Enzyme.Regul. 27: 121 (1988)PubMedCrossRefGoogle Scholar
  7. 7.
    G. Grynkiewicz, N. Poenie, and R. Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties, J.Biol.Chem. 260: 3440 (1985).PubMedGoogle Scholar
  8. 8.
    G. L’Allemain, A. Franchi, E. J. Cragoe jr, and J. Pouyssegur, Blockade of the Na+/H+-antiporter abolishes growth factor induced DNA-synthesis in fibroblasts, J.Biol.Chem. 259: 4313 (1984).PubMedGoogle Scholar
  9. 9.
    S. Grinstein, and A. Rothstein, Mechanism of regulation of the Ne/H+-exchanger, J.Membrane Biol., 90: 1 (1986).CrossRefGoogle Scholar
  10. 10.
    S. Grinstein, J. D. Smith, C. Rowatt, and S. J. Dixon, Mechanism of activation of lymphocyte Na+/H+-exchange by concanavalin A, J.Biol.Chem. 262: 15277 (1987).PubMedGoogle Scholar
  11. 11.
    Y. Nishizuka, Turnover of inositol phospholipids and signal transduction, Science 225: 1365 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    M. J. Berridge, and R. F. Irvine, Inositol tris-phosphate, a novel second messenger in cellular signal transduction, Nature 312: 315 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    S. B. Masters, and H. R. Bourne, Role of G-proteins in transmembrane signaling: Possible functional homology with the ras proteins, in: “Oncogenes and growth control”, P. Kahn, and Th. Graf, eds., Springer Verlag, Berlin (1986).Google Scholar
  14. 14.
    L. F. Fleischman, S. B. Chahwala, and L. Cantley, Ras-transformed cells: Altered levels of phosphatidyl- inositol 4,5-bisphosphate and catabolites, Science 231: 407 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    K. D. Brown, D. M. Blakeley, M. H. Hamon, M. S. Laurie, and A. N. Corps, Protein kinase C mediated negative-feedback inhibition of unstimulated and bombesinstimulated polyphosphoinositide hydrolysis in Swiss mouse 3T3 cells, Biochem.J. 245: 631 (1987).PubMedGoogle Scholar
  16. 16.
    A. Pandiella, L. M. Vicentini, and J. Meldolesi, Protein kinase C mediated feedback inhibition of the Ca2+-response at the EGF-receptor, Biochem.Biophys.Res.Comm. 149: 145 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    W. Siffert, G. Siffert, P. Scheid, T. Riemens, G. Gorter, and J. W. Akkerman, Inhibition of Na+/H+-exchange reduces Ca2+-mobilization without affecting the inositol cleavage of phosphatidylinositol-4,5- bisphosphate in thrombin stimulated platelets, FEBS-Letters 212: 123 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    L. Hunyady, B. Sarkadi, J. R. Cragoe, jr, A. Spat, and G. Gardos, Activation of sodium-proton exchange is not a prerequisite for Ca2+-mobilization and aggregation in human platelets, FEBS-Letters 225: 72 (1987).PubMedCrossRefGoogle Scholar
  19. 19.
    A. W. M. Simpson, and T. J. Rink, Elevation of pHi is not an essential step in calcium mobilization in fura-2loaded human platelets, FEBS-Letters 222: 144 (1987).PubMedCrossRefGoogle Scholar
  20. 20.
    N. E. Owen, and M. L. Villereal, Evidence for a role of calmodulin in serum stimulation of Na+-influx in human fibroblasts, Proc.Natl.Acad.Sci. 79: 3537 (1982).PubMedCrossRefGoogle Scholar
  21. 21.
    G. Parries, R. Hoebel, and E. Racker, Opposing effects of ras-oncogene on growth factor stimulated phosphoinositide hydrolysis: Desensitization of platelet-derived growth factor and enhanced sensitivity to bradykinin, Proc.Natl.Acad.Sci. 84: 2648 (1987).PubMedCrossRefGoogle Scholar
  22. 22.
    J. C. Lacal, J. Moscat, and S. A. Aaronson, Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene, Nature 330: 269 (1987).PubMedCrossRefGoogle Scholar
  23. 23.
    N. Hagag, J. C. Lacal, M. Graber, S. Aaronson, and M. V. Viola, Microinjection of ras p21 induces a rapid rise in intracellular pH, Mol.Cell Biol. 7: 1984 (1987).PubMedGoogle Scholar
  24. 24.
    D. Ozanne, R. J. Fulton, and P. L. Kaplan, Kirsten murine sarcoma virus transformed cell lines and a sponanteously transformed rat cell line produce transforming factors, J.Cell Physiol. 105: 163 (1980)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Hans Grunicke
    • 1
  • Karl Maly
    • 1
  • Hermann Oberhuber
    • 1
  • Wolfgang Doppler
    • 1
  • Johann Hoflacher
    • 1
  • Boris W. Hochleitner
    • 1
  • Rolf Jaggi
    • 2
  • Bernd Groner
    • 2
  1. 1.Institute of Medical Chemistry and BiochemistryUniversity of InnsbruckAustria
  2. 2.Ludwig Institute for Cancer ResearchInselspitalBernSwitzerland

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