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Gene Review

Nras  -  neuroblastoma ras oncogene

Mus musculus

Synonyms: AV095280, GTPase NRas, N-ras, Transforming protein N-Ras
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Disease relevance of Nras

  • In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele [1].
  • Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation [1].
  • By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras [1].
  • Furthermore, lymphomas of Nras single transgenic animals often expressed higher levels of endogenous Skp2 than tumors of double transgenic mice [2].
  • To investigate the relationship between the effects of a pertussis toxin-inhibitable class of G-proteins and the ras family of protooncogenes on cell growth, we isolated multiple cell lines transformed by oncogenic Hras or Nras genes and measured the ability of pertussis toxin to inhibit their growth rate [3].

High impact information on Nras

  • These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression [1].
  • Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor [1].
  • R-ras has at least six exons, with the position of the first intron conserved relative to the Drosophila ras64B and Dictyostelium ras genes; there is no similarity in the exon-intron structure of the R-ras gene and of the mammalian H-, K-, and N-ras proto-oncogenes [4].
  • The active N-ras oncogene coexists with altered versions of the myc oncogene in the HL-60 and AW Ramos human tumors [5].
  • The biological effects of ras oncogene activation in B cells were studied by using amphotropic retroviral vectors to introduce H- or N-ras oncogenes into human B lymphoblasts immortalized by Epstein-Barr virus [6].

Chemical compound and disease context of Nras


Biological context of Nras

  • K-ras is an essential gene in the mouse with partial functional overlap with N-ras [12].
  • Most animals lacking N-ras function and heterozygous for the K-ras mutation exhibit abnormal hematopoietic development and die between days 10 and 12 of embryogenesis [12].
  • The improved differentiation of skeletal muscle in Rb(-/-); N-ras(-/-) embryos occurs despite evidence of deregulated proliferation and apoptosis, as seen in Rb-deficient animals [13].
  • Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development [14].
  • Four different human tissue-derived cell lines, each previously shown to express either a Ha-, Ki-, or N-ras-activated oncogene, were fused in four different paired combinations [15].

Anatomical context of Nras


Associations of Nras with chemical compounds


Physical interactions of Nras


Regulatory relationships of Nras

  • The K-ras gene was preferentially activated over the N-ras gene (approximately 2:1) whether the inducing agent was radiation or the chemical N-nitrosomethylurea [25].
  • Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo [26].
  • Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice [27].
  • Toward understanding the mechanism of action of Krev-1 protein, we constructed a series of point mutants of Krev-1 cDNA and tested their biological activities in DT cells and HT1080 human fibrosarcoma cells harboring the activated N-ras gene [28].
  • c-myc amplification coexistent with activating N-ras point mutation in the biphenotypic leukemic cell line RED-3 [29].

Other interactions of Nras

  • A c-Ha-ras gene was shown to be activated in a myeloid leukaemia and a recently identified member of the 'ras' gene family, N-ras, was found to be activated in a lung carcinoma [30].
  • Primary transfectant DNAs were analyzed by Southern blot hybridization with DNA probes homologous to c-Ha-ras, c-Ki-ras, and N-ras oncogenes [31].
  • We show that deletion of N-ras rescues a unique subset of the developmental defects associated with nullizygosity of Rb, resulting in a significant extension of life span [13].
  • In addition, we have excluded Csf1 and Nras as candidates for both loci [32].
  • This upregulation of mRNA expression paralleled an increase in neurofibromin and N-ras levels, but no change in the relative abundance of the isoforms containing exon 23a or exon 48a was observed during in vitro myoblast differentiation [33].

Analytical, diagnostic and therapeutic context of Nras

  • Northern blot analysis demonstrated equivalent steady-state levels of N-ras transcripts in Hep G2 cells and normal human liver [19].
  • While G35-->A or G35-->T transition detected by PCR and dot-blot hybridization was confirmed by sequencing, the mutations identified similarly at codon 61 in either the Ha- or N-ras oncogenes could not be verified by sequencing of PCR-amplified products subcloned into plasmid vectors [34].
  • Dissection of the mouse N-ras gene upstream regulatory sequences and identification of the promoter and a negative regulatory element [35].
  • Molecular cloning and chromosome assignment of murine N-ras [36].
  • Inactivation of the murine N-ras gene by gene targeting [37].


  1. Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Takahashi, C., Contreras, B., Iwanaga, T., Takegami, Y., Bakker, A., Bronson, R.T., Noda, M., Loda, M., Hunt, J.L., Ewen, M.E. Nat. Genet. (2006) [Pubmed]
  2. Role of the F-box protein Skp2 in lymphomagenesis. Latres, E., Chiarle, R., Schulman, B.A., Pavletich, N.P., Pellicer, A., Inghirami, G., Pagano, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Effect of ras-gene transformation on the inhibition of NIH3T3 cell growth by pertussis toxin. Hildebrandt, J.D., Lederman, L., Steffen, D.L. Mol. Endocrinol. (1991) [Pubmed]
  4. Structure of the human and murine R-ras genes, novel genes closely related to ras proto-oncogenes. Lowe, D.G., Capon, D.J., Delwart, E., Sakaguchi, A.Y., Naylor, S.L., Goeddel, D.V. Cell (1987) [Pubmed]
  5. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Murray, M.J., Cunningham, J.M., Parada, L.F., Dautry, F., Lebowitz, P., Weinberg, R.A. Cell (1983) [Pubmed]
  6. Transformation and plasmacytoid differentiation of EBV-infected human B lymphoblasts by ras oncogenes. Seremetis, S., Inghirami, G., Ferrero, D., Newcomb, E.W., Knowles, D.M., Dotto, G.P., Dalla-Favera, R. Science (1989) [Pubmed]
  7. Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor. Omer, C.A., Chen, Z., Diehl, R.E., Conner, M.W., Chen, H.Y., Trumbauer, M.E., Gopal-Truter, S., Seeburger, G., Bhimnathwala, H., Abrams, M.T., Davide, J.P., Ellis, M.S., Gibbs, J.B., Greenberg, I., Koblan, K.S., Kral, A.M., Liu, D., Lobell, R.B., Miller, P.J., Mosser, S.D., O'Neill, T.J., Rands, E., Schaber, M.D., Senderak, E.T., Oliff, A., Kohl, N.E. Cancer Res. (2000) [Pubmed]
  8. Mutagenesis of ras proto-oncogenes in rat liver tumors induced by vinyl chloride. Froment, O., Boivin, S., Barbin, A., Bancel, B., Trepo, C., Marion, M.J. Cancer Res. (1994) [Pubmed]
  9. Genetic susceptibility to thymic lymphomas and K-ras gene mutation in mice after exposure to X-rays and N-ethyl-N-nitrosourea. Shimada, Y., Nishimura, M., Kakinuma, S., Ogiu, T., Fujimoto, H., Kubo, A., Nagai, J., Kobayash, K., Tano, K., Yoshinaga, S., Bhakat, K.K. Int. J. Radiat. Biol. (2003) [Pubmed]
  10. Rare occurrence of p53 and ras gene mutations in preneoplastic and neoplastic mouse endometrial lesions induced by N-methyl-N-nitrosourea and 17 beta-estradiol. Murase, T., Niwa, K., Morishita, S., Itoh, N., Mori, H., Tanaka, T., Tamaya, T. Cancer Lett. (1995) [Pubmed]
  11. Establishment and characterization of a melanoma cell line from a xeroderma pigmentosum patient: activation of N-ras at a potential pyrimidine dimer site. Keijzer, W., Mulder, M.P., Langeveld, J.C., Smit, E.M., Bos, J.L., Bootsma, D., Hoeijmakers, J.H. Cancer Res. (1989) [Pubmed]
  12. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Johnson, L., Greenbaum, D., Cichowski, K., Mercer, K., Murphy, E., Schmitt, E., Bronson, R.T., Umanoff, H., Edelmann, W., Kucherlapati, R., Jacks, T. Genes Dev. (1997) [Pubmed]
  13. Rb and N-ras function together to control differentiation in the mouse. Takahashi, C., Bronson, R.T., Socolovsky, M., Contreras, B., Lee, K.Y., Jacks, T., Noda, M., Kucherlapati, R., Ewen, M.E. Mol. Cell. Biol. (2003) [Pubmed]
  14. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Esteban, L.M., Vicario-Abejón, C., Fernández-Salguero, P., Fernández-Medarde, A., Swaminathan, N., Yienger, K., Lopez, E., Malumbres, M., McKay, R., Ward, J.M., Pellicer, A., Santos, E. Mol. Cell. Biol. (2001) [Pubmed]
  15. Suppression of tumorigenicity in human cell hybrids derived from cell lines expressing different activated ras oncogenes. Geiser, A.G., Anderson, M.J., Stanbridge, E.J. Cancer Res. (1989) [Pubmed]
  16. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. End, D.W., Smets, G., Todd, A.V., Applegate, T.L., Fuery, C.J., Angibaud, P., Venet, M., Sanz, G., Poignet, H., Skrzat, S., Devine, A., Wouters, W., Bowden, C. Cancer Res. (2001) [Pubmed]
  17. Protooncogene expression in normal, preleukemic, and leukemic murine erythroid cells and its relationship to differentiation and proliferation. Robert-Lézénès, J., Meneceur, P., Ray, D., Moreau-Gachelin, F. Cancer Res. (1988) [Pubmed]
  18. Immunohistochemical staining of ras oncogene product in neoplastic and non-neoplastic mesothelial tissues: immunoreactivity for N-ras and lack of immunohistochemical staining for Ha-ras and K-ras. Ramael, M., Deblier, I., Eerdekens, C., Lemmens, G., Jacobs, W., Van Marck, E. J. Pathol. (1993) [Pubmed]
  19. Characterization of a transforming N-ras gene in the human hepatoma cell line Hep G2: additional evidence for the importance of c-myc and ras cooperation in hepatocarcinogenesis. Richards, C.A., Short, S.A., Thorgeirsson, S.S., Huber, B.E. Cancer Res. (1990) [Pubmed]
  20. Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice. Manam, S., Storer, R.D., Prahalada, S., Leander, K.R., Kraynak, A.R., Ledwith, B.J., van Zwieten, M.J., Bradley, M.O., Nichols, W.W. Cancer Res. (1992) [Pubmed]
  21. Positive autoregulation of ras genes expression in fibroblasts. Quincoces, A.F., Polanco, I., Thomson, T., León, J. FEBS Lett. (1997) [Pubmed]
  22. Effects of SCH 59228, an orally bioavailable farnesyl protein transferase inhibitor, on the growth of oncogene-transformed fibroblasts and a human colon carcinoma xenograft in nude mice. Liu, M., Bryant, M.S., Chen, J., Lee, S., Yaremko, B., Li, Z., Dell, J., Lipari, P., Malkowski, M., Prioli, N., Rossman, R.R., Korfmacher, W.A., Nomeir, A.A., Lin, C.C., Mallams, A.K., Doll, R.J., Catino, J.J., Girijavallabhan, V.M., Kirschmeier, P., Bishop, W.R. Cancer Chemother. Pharmacol. (1999) [Pubmed]
  23. Plasmid-aided insertion of MMTV-LTR and ras DNAs to NIH 3T3 fibroblast cells makes them responsive to 2,3,7,8-TCDD causing overexpression of p21ras and down-regulation of EGF receptor. Jankun, J., Matsumura, F., Kaneko, H., Trosko, J.E., Pellicer, A., Greenberg, A.H. Molecular toxicology. (1989) [Pubmed]
  24. Myb binding sites within the N-ras promoter repress transcription. Ganter, B., Lipsick, J.S. Oncogene (1997) [Pubmed]
  25. Radiation and chemical activation of ras oncogenes in different mouse strains. Newcomb, E.W., Diamond, L.E., Sloan, S.R., Corominas, M., Guerrerro, I., Pellicer, A. Environ. Health Perspect. (1989) [Pubmed]
  26. Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Hamilton, M., Wolfman, A. Oncogene (1998) [Pubmed]
  27. Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. Borner, C., Schlagbauer Wadl, H., Fellay, I., Selzer, E., Polterauer, P., Jansen, B. Melanoma Res. (1999) [Pubmed]
  28. Genetic analysis of the Kirsten-ras-revertant 1 gene: potentiation of its tumor suppressor activity by specific point mutations. Kitayama, H., Matsuzaki, T., Ikawa, Y., Noda, M. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  29. c-myc amplification coexistent with activating N-ras point mutation in the biphenotypic leukemic cell line RED-3. Mallet, M.K., Mane, S.M., Meltzer, S.J., Needleman, S.W. Leukemia (1989) [Pubmed]
  30. Three different activated ras genes in mouse tumours; evidence for oncogene activation during progression of a mouse lymphoma. Vousden, K.H., Marshall, C.J. EMBO J. (1984) [Pubmed]
  31. Identification of an activated c-Ki-ras oncogene in rat liver tumors induced by aflatoxin B1. McMahon, G., Hanson, L., Lee, J.J., Wogan, G.N. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  32. Mapping by genetic interaction: high-resolution congenic mapping of the type 1 diabetes loci Idd10 and Idd18 in the NOD mouse. Lyons, P.A., Armitage, N., Lord, C.J., Phillips, M.S., Todd, J.A., Peterson, L.B., Wicker, L.S. Diabetes (2001) [Pubmed]
  33. Modulation of neurofibromatosis type 1 gene expression during in vitro myoblast differentiation. Gutmann, D.H., Cole, J.L., Collins, F.S. J. Neurosci. Res. (1994) [Pubmed]
  34. Mutations in ras oncogenes: rare events in ultraviolet B radiation-induced mouse skin tumorigenesis. Khan, S.G., Mohan, R.R., Katiyar, S.K., Wood, G.S., Bickers, D.R., Mukhtar, H., Agarwal, R. Mol. Carcinog. (1996) [Pubmed]
  35. Dissection of the mouse N-ras gene upstream regulatory sequences and identification of the promoter and a negative regulatory element. Paciucci, R., Pellicer, A. Mol. Cell. Biol. (1991) [Pubmed]
  36. Molecular cloning and chromosome assignment of murine N-ras. Ryan, J., Hart, C.P., Ruddle, F.H. Nucleic Acids Res. (1984) [Pubmed]
  37. Inactivation of the murine N-ras gene by gene targeting. Cases, S., Dautry, F. Oncogene (1992) [Pubmed]
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