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RAS oncogenes: the first 30 years

A Correction to this article was published on 01 September 2003

Abstract

From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction — mainly in human cancer — is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.

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Figure 1: Schematic representation of our current view of RAS regulation.
Figure 2: Overview of known RAS effectors and their corresponding biological responses.

References

  1. Harvey, J. J. An unidentified virus which causes the rapid production of tumors in mice. Nature 204, 1104–1105 (1964).

    CAS  PubMed  Google Scholar 

  2. Kirsten, W. H. & Mayer, L. A. Morphologic responses to a murine erythroblastosis virus. J. Natl Cancer Inst. 39, 311–335 (1967).

    CAS  PubMed  Google Scholar 

  3. Peters, R. L., Rabstein, L. S., VanVleck, R., Kelloff, G. J. & Huebner, R. J. Naturally occurring sarcoma virus of the BALB/cCr mouse. J. Natl Cancer Inst. 53, 1725–1729 (1974).

    CAS  PubMed  Google Scholar 

  4. Rasheed, S., Gardner, M. B. & Huebner, R. J. In vitro isolation of stable rat sarcoma viruses. Proc. Natl Acad. Sci. USA 75, 2972–2976 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Scolnick, E. M., Rands, E., Williams, D. & Parks, W. P. Studies on the nucleic acid sequences of Kirsten sarcoma virus: a model for formation of a mammalian RNA-containing sarcoma virus. J. Virol. 12, 458–463 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hager, G. L. et al. Molecular cloning of the Harvey sarcoma virus closed circular DNA intermediates: initial structural and biological characterization. J. Virol. 31, 795–809 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Tsuchida, N. & Uesugi, S. Structure and functions of the Kirsten murine sarcoma virus genome: molecular cloning of biologically active Kirsten murine sarcoma virus DNA. J. Virol. 38, 720–727 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ellis, R. W. et al. The p21 src genes of Harvey and Kirsten murine sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature 292, 506–511 (1981).

    CAS  PubMed  Google Scholar 

  9. Wigler, M., Pellicer, A., Silverstein, S. & Axel, R. Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor. Cell 14, 725–731 (1978).

    CAS  PubMed  Google Scholar 

  10. Shih, C., Shilo, B. Z., Goldfarb, M. P., Dannenberg, A. & Weinberg, R. A. Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc. Natl Acad. Sci. USA 76, 5714–5718 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shih, C., Padhy, L. C., Murray, M. & Weinberg, R. A. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290, 261–264 (1981).

    CAS  PubMed  Google Scholar 

  12. Perucho, M. et al. Human-tumor-derived cell lines contain common and different transforming genes. Cell 27, 467–476 (1981).

    CAS  PubMed  Google Scholar 

  13. Shih, C. & Weinberg, R. A. Isolation of a transforming sequence from a human bladder sarcoma cell line. Cell 29, 161–169 (1982).

    CAS  PubMed  Google Scholar 

  14. Goldfarb, M., Shimizu, K., Perucho, M. & Wigler, M. Isolation and preliminary characterization of a human transforming gene from T24 bladder carcinoma cells. Nature 296, 404–409 (1982).

    CAS  PubMed  Google Scholar 

  15. Pulciani, S. et al. Oncogenes in human tumor cell lines: molecular cloning of a transforming gene from human bladder carcinoma cells. Proc. Natl Acad. Sci. USA 79, 2845–2849 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Der, C. J., Krontiris, T. G. & Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 3637–3640 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras. Nature 297, 474–478 (1982).

    CAS  PubMed  Google Scholar 

  18. Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S. & Barbacid, M. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298, 343–347 (1982).

    CAS  PubMed  Google Scholar 

  19. Parada, L. F. & Weinberg, R. A. Presence of a Kirsten murine sarcoma virus ras oncogene in cells transformed by 3-methylcholanthrene. Mol. Cell. Biol. 3, 2298–2301 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Shimizu, K., Goldfarb, M., Perucho, M. & Wigler, M. Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line. Proc. Natl Acad. Sci. USA 80, 383–387 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hall, A., Marshall, C. J., Spurr, N. K. & Weiss, R. A. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature 303, 396–400 (1983).

    CAS  PubMed  Google Scholar 

  22. Reddy, E. P., Reynolds, R. K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).

    CAS  PubMed  Google Scholar 

  23. Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–147 (1982).

    CAS  PubMed  Google Scholar 

  24. Taparowsky, E. et al. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300, 762–765 (1982).

    CAS  PubMed  Google Scholar 

  25. Muschel, R. J., Khoury, G., Lebowitz, P., Koller, R. & Dhar, R. The human c-ras1H oncogene: a mutation in normal and neoplastic tissue from the same patient. Science 219, 853–856 (1983).

    CAS  PubMed  Google Scholar 

  26. Duesberg, P. H. Activated proto-onc genes: sufficient or necessary for cancer? Science 228, 669–677 (1985).

    CAS  PubMed  Google Scholar 

  27. Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–602 (1983).

    Article  CAS  PubMed  Google Scholar 

  28. Newbold, R. F. & Overell, R. W. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304, 648–651 (1983).

    CAS  PubMed  Google Scholar 

  29. Ruley, H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304, 602–606 (1983).

    CAS  PubMed  Google Scholar 

  30. Santos, E. et al. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 223, 661–664 (1984).

    CAS  PubMed  Google Scholar 

  31. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  Google Scholar 

  32. Bos, J. L. et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 327, 293–297 (1987).

    CAS  PubMed  Google Scholar 

  33. Forrester, K., Almoguera, C., Han, K., Grizzle, W. E. & Perucho, M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327, 298–303 (1987).

    CAS  PubMed  Google Scholar 

  34. Rodenhuis, S. et al. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N. Engl. J. Med. 317, 929–935 (1987).

    CAS  PubMed  Google Scholar 

  35. Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).

    CAS  PubMed  Google Scholar 

  36. Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983).

    CAS  PubMed  Google Scholar 

  37. Sukumar, S., Notario, V., Martin-Zanca, D. & Barbacid, M. Induction of mammary carcinomas in rats by nitroso-methyl-urea involves the malignant activation of the H-ras-1 locus by single point mutations. Nature 306, 658–661 (1983).

    CAS  PubMed  Google Scholar 

  38. Guerrero, I., Calzada, P., Mayer, A. & Pellicer, A. A molecular approach to leukemogenesis: mouse lymphomas contain an activated c-ras oncogene. Proc. Natl Acad. Sci. USA 81, 202–205 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Parks, W. P. & Scolnick, E. M. In vitro translation of Harvey murine sarcoma virus RNA. J. Virol. 22, 711–719 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shih, T. Y., Weeks, M. O., Young, H. A. & Scolnick, E. M. p21 of Kirsten murine sarcoma virus is thermolabile in a viral mutant temperature sensitive for the maintenance of transformation. J. Virol. 31, 546–546 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shih, T. Y., Weeks, M. O., Young, H. A. & Scolnick, E. M. Identification of a sarcoma virus-coded phosphoprotein in nonproducer cells tranformed by Kirsten or Harvey murine sarcoma virus. Virology 96, 64–79 (1979).

    CAS  PubMed  Google Scholar 

  42. Scolnick, E. M., Papageorge, A. G. & Shih, T. Y. Guanine nucleotide-binding activity as an assay for src protein of rat-derived murine sarcoma viruses. Proc. Natl Acad. Sci. USA 76, 5355–5359 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Willingham, M. C., Pastan, I., Shih, T. Y. & Scolnick, E. M. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell 19, 1005–1014 (1980).

    CAS  PubMed  Google Scholar 

  44. Willumsen, B. M., Christensen, A., Hubbert, H. L., Papageorge, A. G. & Lowy, D. R. The p21ras c-terminus is required for transformation and membrane association. Nature 310, 583–586 (1984).

    CAS  PubMed  Google Scholar 

  45. Gibbs, J. B., Sigal, I. S., Poe, M. & Scolnick, E. M. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc. Natl Acad. Sci. USA 81, 5704–5708 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. McGrath, J. P., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310, 644–649 (1984).

    CAS  PubMed  Google Scholar 

  47. Sweet, R. W. et al. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature 311, 273–275 (1984).

    CAS  PubMed  Google Scholar 

  48. Hurley, J. B., Simon, M. I., Teplow, D. B., Robishaw, J. D. & Gilman, A. G. Homologies between signal transducing G proteins and ras gene products. Science 226, 860–862 (1984).

    CAS  PubMed  Google Scholar 

  49. Toda, T. et al. In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell 40, 27–36 (1985).

    CAS  PubMed  Google Scholar 

  50. Kamata, T. & Feramisco, J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).

    CAS  PubMed  Google Scholar 

  51. Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985).

    CAS  PubMed  Google Scholar 

  52. Smith, M. R., DeGudicibus, S. J. & Stacey, D. W. Requirement for c-Ras proteins during viral oncogene transformation. Nature 320, 540–543 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Birchmeier, C., Broek, D. & Wigler, M. ras proteins can induce meiosis in Xenopus oocytes. Cell 43, 615–621 (1985).

    CAS  PubMed  Google Scholar 

  54. Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542–545 (1987).

    CAS  PubMed  Google Scholar 

  55. Trahey, M. et al. Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242, 1697–1700 (1988).

    CAS  PubMed  Google Scholar 

  56. Vogel, U. S. et al. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335, 90–93 (1988).

    CAS  PubMed  Google Scholar 

  57. Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).

    CAS  PubMed  Google Scholar 

  58. Martin, G. A. et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849 (1990).

    CAS  PubMed  Google Scholar 

  59. Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    CAS  PubMed  Google Scholar 

  60. Xu, G. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).

    CAS  PubMed  Google Scholar 

  61. Broek, D. et al. The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell 48, 789–799 (1987).

    CAS  PubMed  Google Scholar 

  62. Robinson, L. C., Gibbs, J. B., Marshall, M. S., Sigal, I. S. & Tatchell, K. CDC25: a component of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235, 1218–1221 (1987).

    CAS  PubMed  Google Scholar 

  63. Wolfman, A. & Macara, I. G. A cytosolic protein catalyzes the release of GDP from p21ras. Science 248, 67–69 (1990).

    CAS  PubMed  Google Scholar 

  64. Downward, J., Riehl, R., Wu, L. & Weinberg, R. A. Identification of a nucleotide exchange-promoting activity for p21ras. Proc. Natl Acad. Sci. USA 87, 5998–6002 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Martegani, E. et al. Cloning by functional complementation of a mouse cDNA encoding a homologue of CDC25, a Saccharomyces cerevisiae RAS activator. EMBO J. 11, 2151–2157 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bowtell, D., Fu, P., Simon, M. & Senior, P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc. Natl Acad. Sci. USA 89, 6511–6515 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Shou, C., Farnsworth, C. L., Neel, B. G. & Feig, L. A. Molecular cloning of cDNAs encoding a guanine-releasing factor for ras p21. Nature 358, 351–354 (1992).

    CAS  PubMed  Google Scholar 

  68. Wei, W. et al. Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 89, 7100–7104 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Clark, S. G., Stern, M. J. & Horvitz, H. R. C. elegans cell-signalling gene Sem-5 encodes a protein with SH2 and SH3 domains. Nature 356, 340–344 (1992).

    CAS  PubMed  Google Scholar 

  70. Lowenstein, E. J. et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to Ras signalling. Cell 70, 431–442 (1992).

    CAS  PubMed  Google Scholar 

  71. Matuoka, K., Shibata, M., Yamakawa, A. & Takenawa, T. Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries. Proc. Natl Acad. Sci. USA 89, 9015–9019 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. McCormick, F. Signal transduction. How receptors turn Ras on. Nature 363, 15–16 (1993).

    CAS  PubMed  Google Scholar 

  73. Rapp, U. R. & Todaro, G. J. Generation of oncogenic mouse type C viruses: in vitro selection of carcinoma-inducing variants. Proc. Natl Acad. Sci. USA 77, 624–628 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Moodie, S. A., Willumsen, B. M., Weber, M. J. & Wolfman, A. Complexes of Ras. GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260, 1658–1661 (1993).

    CAS  PubMed  Google Scholar 

  75. Warne, P. H., Rodriguez-Viciana, P. & Downward, J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364, 352–355 (1993).

    CAS  PubMed  Google Scholar 

  76. Zhang, X. F. et al. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364, 308–313 (1993).

    CAS  PubMed  Google Scholar 

  77. Vojitek, A. B., Hollenbarg, S. M. & Cooper, J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74, 205–214 (1993).

    Google Scholar 

  78. Han, M., Golden, A., Han, Y. & Sternberg, P. W. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 363, 133–140 (1993).

    CAS  PubMed  Google Scholar 

  79. Sjolander, A., Yamamoto, K., Huber, B. E. & Lapetina, E. G. Association of p21ras with phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 88, 7908–7912 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kazlauskas, A. Receptor tyrosine kinases and their targets. Curr. Opin. Genet. Dev. 4, 5–14 (1994).

    CAS  PubMed  Google Scholar 

  81. Rodríguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target for ras. Nature 370, 527–532 (1994).

    PubMed  Google Scholar 

  82. Hofer, F., Fields, S., Schneider, C. & Martin, G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc. Natl Acad. Sci. USA 91, 11089–11093 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kikuchi, A., Demo, S. D., Ye, Z. H., Chen, Y. W. & Williams, L. T. ralGDS family members interact with the effector loop of ras p21. Mol. Cell. Biol. 14, 7483–7491 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Spaargaren, M. & Bischoff, J. R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc. Natl Acad. Sci. USA 91, 12609–12613 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Schafer, W. R. et al. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science 245, 379–385 (1989).

    CAS  PubMed  Google Scholar 

  86. Schafer, W. R. et al. Enzymatic coupling of cholesterol intermediates to a mating pheromone precursor and to the ras protein. Science 249, 1133–1139 (1990).

    CAS  PubMed  Google Scholar 

  87. Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J. & Brown, M. S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81–88 (1990).

    CAS  PubMed  Google Scholar 

  88. Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995).

    CAS  PubMed  Google Scholar 

  89. Nagasu, T., Yoshimatsu, K., Rowell, C., Lewis, M. D. & Garcia. A. M. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res. 55, 5310–5314 (1995).

    CAS  PubMed  Google Scholar 

  90. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nature Rev. Cancer 3, 11–22 (2003).

    CAS  Google Scholar 

  91. Vos, A. M. et al. Three-dimensional structure of an oncogene protein: catalytic domain of human c-H-ras p21. Science 239, 888–893 (1988).

    PubMed  Google Scholar 

  92. Pai, E. F. et al. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341, 209–214 (1989).

    CAS  PubMed  Google Scholar 

  93. Schlichting, I. et al. Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature 345, 309–315 (1990).

    CAS  PubMed  Google Scholar 

  94. Krengel, U. et al. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell 62, 539–548 (1990).

    CAS  PubMed  Google Scholar 

  95. Tong, L. A., de Vos, A. M., Milburn, M. V. & Kim, S. H. Crystal structures at 2.2 Å resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP. J. Mol. Biol. 217, 503–516 (1991).

    CAS  PubMed  Google Scholar 

  96. Scheffzek, K. et al. The Ras-RasGAP complex: structural basis for GTPase activation and itss loss in oncogenic Ras mutants. Science 277, 333–338 (1997).

    CAS  PubMed  Google Scholar 

  97. Ahmadian, M. R. et al. Guanosine triphosphatase stimulation of oncogenic Ras mutants. Proc. Natl Acad. Sci. USA 96, 7065–7070 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Boriack-Sjodin, P. A. et al. The structural basis of the activation of Ras by Sos. Nature 394, 337–343 (1998).

    CAS  PubMed  Google Scholar 

  99. Huang, L., Hofer, F., Martin, G. S. & Kim, S. H. Structural basis for the interaction of Ras with RalGDS. Nature Struct. Biol. 5, 422–426 (1998).

    CAS  PubMed  Google Scholar 

  100. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103, 931–943 (2000).

    CAS  PubMed  Google Scholar 

  101. Reuther, G. W. & Der, C. J. The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr. Opin. Cell Biol. 12, 157–165 (2000).

    CAS  PubMed  Google Scholar 

  102. Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Koera, K. et al. K-ras is essential for the development of the mouse embryo. Oncogene 15, 1151–1159 (1997).

    CAS  PubMed  Google Scholar 

  104. Esteban, L. M. et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol. 21, 1444–1452 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bivona, T. G. & Philips, M. R. Ras pathway signaling on endomembranes. Curr. Opin. Cell Biol. 15, 136–142 (2003).

    CAS  PubMed  Google Scholar 

  106. Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    CAS  PubMed  Google Scholar 

  108. Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984).

    CAS  PubMed  Google Scholar 

  109. Zarbl, H., Sukumar, S., Arthur, A., Martin-Zanca, D. & Barbacid, M. Direct mutagenesis of H-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats. Nature 315, 382–385 (1985).

    CAS  PubMed  Google Scholar 

  110. Wiseman, R. W., Stowers, S. J., Miller, E. C., Anderson, M. W. & Miller, J. A. Activating mutations of the c-Ha-ras protooncogene in chemically induced hepatomas of the male B6C3 F1 mouse. Proc. Natl Acad. Sci. USA 83, 5825–5829 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    CAS  PubMed  Google Scholar 

  112. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    CAS  PubMed  Google Scholar 

  114. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R. & Leder, P. Coexpression of MMTV/v-Ha-ras and MMTV/ c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49, 465–475 (1987).

    CAS  PubMed  Google Scholar 

  116. Quaife, C. J., Pinkert, C. A., Ornitz, D. M., Palmiter, R. D. & Brinster, R. L. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 48, 1023–1034 (1987).

    CAS  PubMed  Google Scholar 

  117. Umanoff, H., Edelmann, W., Pellicer, A. & Kucherlapati, R. The murine N-ras gene is not essential for growth and development. Proc. Natl Acad. Sci. USA 92, 1709–1713 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Pérez de Castro, I. et al. Mice deficient for N-ras: impaired antiviral immune response and T-cell function. Cancer Res. 63, 1615–1622 (2003).

    PubMed  Google Scholar 

  119. Ise, K. et al. Targeted deletion of the H–ras gene decreases tumor formation in mouse skin carcinogenesis. Oncogene 19, 2951–2956 (2000).

    CAS  PubMed  Google Scholar 

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Correspondence to Marcos Malumbres or Mariano Barbacid.

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RAS in human disease

Structural biology of RAS

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Malumbres, M., Barbacid, M. RAS oncogenes: the first 30 years. Nat Rev Cancer 3, 459–465 (2003). https://doi.org/10.1038/nrc1097

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