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Interfering with Ras Signaling Using Membrane-Permeable Peptides or Drugs

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Part of the Methods in Molecular Biology™ book series (MIMB, volume 189)

Abstract

During the last two decades since the first oncogene product called v-Src was identified as a constitutively activated mutant of a normal mitogenic gene (proto-oncogene) encoding a Tyr kinase called c-Src in early 1980s, it was firmly established that the malignant transformation of normal cells is caused by a combination of the following genetic events: overexpression of a protooncogene or constitutive activation of its gene product (mitogenic signal transducer), and deletion of a tumor-suppressor gene (also called anti-oncogene or anti-mitogenic gene) or dysfunction of its gene product (anti-mitogenic signal transducer).

Keywords

Soft Agar Assay Distinct Effector Mitogenic Signal Transducer Peptide Vector High Affinity Mutant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. 1.
    Bos, J. L. (1989) Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689.PubMedGoogle Scholar
  2. 2.
    Downward, J. (1998) Oncogenic RAS signaling network, in G Proteins, Cytoskel-eton and Cancer (Maruta, H. and Kohama, K., eds.), Landes Bioscience, Austin, TX, pp. 171–183.Google Scholar
  3. 3.
    Qiu, R., Che, J., Kirn, D., McCormick, F., and Symons, M. (1995) An essential role for Rac in RAS transformation. Nature 374, 457–459.PubMedCrossRefGoogle Scholar
  4. 4.
    Qiu, R., Abo, A., McCormick, F., and Symons, M. (1997) CDC42 regulates anchorage-independent growth and is necessary for RAS transformation. Mol. CellBiol. 17, 3449–3458.Google Scholar
  5. 5.
    Lilienthal, J., Moon, S. Y., Lesche, R., Mammillapalli, R., Li, D., et al (2000) Genetic deletion of the PTEN tumor suppressor gene promotes cell motility by activation of Rac and CDC42 GTPases. Curr. Biol. 10, 401–404.CrossRefGoogle Scholar
  6. 6.
    Nur-E-Kamal, M. S. A., Kamal, J., Quresh, M., and Maruta, H. (1999) The CDC42-specific inhibitor derived from ACK-1 blocks v-Ha-RAS-induced transformation. Oncogene 18, 7787–7793.PubMedCrossRefGoogle Scholar
  7. 7.
    Manser, E., Leung, T., Salihuddin, H., Tan, L, and Lim, L. (1993) A nonreceptor Tyr kinase that inhibits the GTPase activity of CDC42. Nature 363, 364–367.PubMedCrossRefGoogle Scholar
  8. 8.
    Manser, E., Leung, T., Salihuddin, H., Zhao, Z., and Lim, L. (1994) A brain Ser/Thr kinase activated by CDC42 and Rac. Nature 367, 40–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Symons, M., Derry, J., Karlak, B., Jiang, S., Lemahieu, V., and McCormick, F. (1996) Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42, is implicated in actin polymerization. Cell 84, 723–734.PubMedCrossRefGoogle Scholar
  10. 10.
    Miki, H., Sasaki, T., Takai, Y., and Takenawa, T. (1998) Induction of filopodium formation by a WASP-related actin depolymerizing protein N-WASP. Nature 391, 93–96.PubMedCrossRefGoogle Scholar
  11. 11.
    Van Aelst, L., Joneson, T., and Bar-Sagi, D. (1996) Identification of a novel Rac-interacting protein involved in membrane ruffling. EMBO J. 15, 3778–3786.PubMedGoogle Scholar
  12. 12.
    Kobayashi, K., Kuroda, S., Fukata, M., Nakamura T., Nagase, T., et al. (1998) P140Sra-1 (specifically Rac-associated protein) is a novel specific target for Rac GTPase. J. Biol. Chem. 273, 291–295.PubMedCrossRefGoogle Scholar
  13. 13.
    Daniels, R., Zenke, F., and Bokoch, G. (1999) PIX stimulates PAK kinase activity through exchange factor-dependent and independent mechanisms. J. Biol. Chem. 274, 6047–6050.PubMedCrossRefGoogle Scholar
  14. 14.
    Manser, E., Loo, T., Koh, C., Zhao, Z., Chen, X., et al. (1998) PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol. Cell 1, 183–192.PubMedCrossRefGoogle Scholar
  15. 15.
    Obermeier, A., Ahmed, S., Manser, E., Yen, S., Hall, C., and Lim, L.(1998) PAK promotes morphological changes by actin upstream of Rac. EMBO J. 17, 4328–4339.PubMedCrossRefGoogle Scholar
  16. 16.
    Maruta, H., He, H., Anjali, T., and Nur-E-Kamal, M. S. A. (1999) Cytoskeletal tumor suppressors that block oncogenic RAS signaling. Ann. NYAcad. Sci. 886, 48–57.CrossRefGoogle Scholar
  17. 17.
    Derossi, D., Chassaing, G., and Prochiantz, A. (1998) Trojan peptides: the penetratin system for intracellular delivery. Trends CellBiol. 8, 84–87.Google Scholar
  18. 18.
    Joliot, A., Pernelle, C., Deagostini-Bazin, H., and Pronchiantz, A. (1991) Anten-napedia homeobox peptide regulates neural morphogenesis. Proc. Nat. Acad. Sci. USA 88, 1864–1868.PubMedCrossRefGoogle Scholar
  19. 19.
    Derossi, D., Joliot, A., Chassaing, G., and Prochiantz, A. (1994) The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269, 10,444–10,450.PubMedGoogle Scholar
  20. 20.
    Williams, E., Dunican, D., Green, P., Howell, F., and Derossi, D. (1997) Selective inhibition of growth factor-stimulated mitogenesis by a cell-permeable Grb-2-binding peptide. J. Biol. Chem. 272, 22,349–22,354.PubMedCrossRefGoogle Scholar
  21. 21.
    He, H., Hirokawa, Y., Levitzki, A., and Maruta, H. (2000) An anti-RAS cancer potential of PP1, an inhibitor specific for SRC family kinases: in vitro and in vivo studies. Cancer J. Sci. Am. 6, 243–248.Google Scholar
  22. 22.
    He, H., Hirokawa, Y., Manser, E., et al. (2001) Signal therapy of RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Cancer J. 7, 191–202.PubMedGoogle Scholar
  23. 23.
    Maruta, H., He, H., Tikoo, A., Vuong-Nheu, T., and Nur-E-Kamal, M. S. A. (1999) G proteins, phosphatidylinositides, actin-cytoskeleton in the control of cancer growth. Microsc. Res. Tech. 47, 61–66.PubMedCrossRefGoogle Scholar
  24. 24.
    Glick, A., Sporn, M., and Yuspa, S. (1991) Altered regulation of TGFβ-1 and TGFα in primary keratinocytes and papillomas expressing v-Ha-RAS. Mol. Carcinog. 4, 210–219.PubMedCrossRefGoogle Scholar
  25. 25.
    Higashiyama, S., Abraham, J., Miller, J., Fiddes, J., and Klagsbrun, M. (1991) A heparin-binding growth factor secreted by macrophage-like cells is related to EGF. Science 251, 936–939.PubMedCrossRefGoogle Scholar
  26. 26.
    Normanno, N., Selvan, M., Qi, C., Saeki, T., Johnson, G., et al. (1994) Amphi-regulin as an autocrine growth factor for c-Ha-Ras /c-ErbB2-transformed human mammary epithelial cells. Proc. Nat. Acad. Sci. USA 91, 2790–2794.PubMedCrossRefGoogle Scholar
  27. 27.
    Mincione, G., Bianco, C., Kannan, S., Colletta, G., Ciardiello, F., et al. (1996) Enhanced expression of heregulin in ErbB2 and c-Ha-RAS transformed mouse and human mammary epithelial cells. J. Cell Biochem. 60, 437–446.PubMedCrossRefGoogle Scholar
  28. 28.
    Levitzki A. and Gazit A. (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267, 1782–1788.PubMedCrossRefGoogle Scholar
  29. 29.
    Hanke, J., Gardner, J., Dow, R., Changelian, P., Brissette, W., et al. (1996) Discovery of a novel, potent, and Src family-selective Tyr kinase inhibitor. J. Biol. Chem. 271, 695–701.Google Scholar
  30. 30.
    Maruta, H., Holden, J., Sizeland, A., and D’Abaco, G. (1991) The residues of RAS and Rap proteins that determine their GAP activities. J. Biol. Chem. 266, 11,661–11,668.PubMedGoogle Scholar
  31. 31.
    Tang, Y., Yu, J., and Field, J. (1999) Signals from the RAS, Rac and Rho GTPases converge on the PAK kinase in Rat-1 fibroblasts. Mol. Cell Biol. 19, 1881–1891.PubMedGoogle Scholar
  32. 32.
    Tikoo, A., Shakri, R., Connolly, L., Hirokawa, Y., Shishido, T., et al. (2000) Treatment of RAS-induced cancers by the F-actin bundling drug MKT-077. Cancer J. 6, 162–168.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  1. 1.Tumor Suppressor LaboratoryLudwig Institute for Cancer ResearchMelbourneAustralia

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