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Gene Review

ras  -  Ras protein

Xenopus laevis

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Disease relevance of ras

  • We have shown that this 25K protein has a sequence homologous to the translated reading frame of TC4, a cDNA found by screening a human teratocarcinoma cDNA library with oligonucleotides coding for a ras consensus sequence, and that the protein binds GDP and GTP [1].
  • When the xlcaax-1 cDNA is expressed in a baculovirus expression system, the product undergoes isoprenylation and palmitoylation utilizing a mechanism similar to that of the ras proteins [2].
  • Mutational activation of ras has been found in many types of human cancers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas [3].
  • The lethal toxin (LT) from Clostridium sordellii is a glucosyltransferase that modifies and inhibits small G proteins of the Ras family, Ras and Rap, as well as Rac proteins [4].

High impact information on ras

  • ras proteins can induce meiosis in Xenopus oocytes [5].
  • We report here that a dominant inhibitory ras mutant blocks the mesoderm-inducing activity of fibroblast growth factor and activin, as well as the endogenous inducing activity of prospective endoderm [6].
  • The ras-encoded p21ras proteins bind GTP very tightly, but catalyse hydrolysis to GDP very slowly [7].
  • The pattern of inhibition indicated that M protein interfered with transport that is dependent on the ras-like nuclear guanosine triphosphatase (GTPase) Ran-TC4 and its associated factors [8].
  • This induction occurs without a stimulation of overall protein synthesis and is blocked by the co-expression of a dominant negative mutant of the proto-oncogene ras or a truncated activin type II receptor [9].

Biological context of ras

  • The ras oncoprotein and M-phase activity [10].
  • These proteins acquire transforming properties as a result of activating lesions that convert ras genes to oncogenes in a wide array of malignancies [11].
  • The p21 products of ras proto-oncogenes are thought to be important components in pathways regulating normal cell proliferation and differentiation [11].
  • Evidence is accumulating that the rho family, a member of the ras p21-related small GTP-binding protein superfamily, regulates cell morphology, cell motility, and smooth muscle contraction through the actomyosin system [12].
  • These findings suggest that ras proteins activate the pathway linked to S6 phosphorylation and that protein kinase C has a synergistic effect on the ras-mediated pathway [13].

Anatomical context of ras

  • To identify the direct target molecule of ras p21 in higher eukaryotes, we have recently developed the cell-free system in which ras p21 activates mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) [14].
  • Thus the immunochemical data and microinjection experiments suggest that ras-like or ras antigenicity exists within rapidly replicating Xenopus blastomeres and may be involved in the organization of a number of its cytoplasmic elements [15].
  • In vitro studies indicated that the scFv is expressed in the cytosol of Xenopus laevis oocytes and of tumor cells, blocks ras-mediated activation processes, and induces tumor cell death [16].
  • Smooth muscle alpha-actin promoter is repressed in ras-transformed fibroblast cells and derepressed in revertant cells [17].
  • It is this activation of Ras/MAPK that is required for neuralization in dissociated ectoderm [18].

Associations of ras with chemical compounds

  • These observations establish a connection between the cholesterol biosynthetic pathway and transformation by the ras oncogene and offer a novel pharmacological approach to investigating, and possibly controlling, ras-mediated malignant transformations [19].
  • The role of guanine nucleotides in ras p21 function was determined by using the ability of p21 protein to induce maturation of Xenopus oocytes as a quantitative assay for biological activity [20].
  • By use of the Xenopus oocyte system, it was possible to quantitate the effects of ras p21 microinjection on individual components of the phosphoinositide pathway [11].
  • Azatyrosine has been shown by others [Shindo-Okada, N., Makabe, O., Nagahara, H. & Nishimura, S. (1989) Mol. Carcinog. 2, 159-167] to inhibit the growth of ras-transformed cells without affecting that of nontransformed cells [21].
  • Induction of meiosis by ras was compared with induction by progesterone, insulin, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) [22].

Regulatory relationships of ras

  • Oncogenic ras stimulates a 96-kDa histone H2b kinase activity in activated Xenopus egg extracts. Correlation with the suppression of p34cdc2 kinase [23].

Other interactions of ras

  • Proto-oncogenes raf and the ras family, N-ras, H-ras and c-ral, gave the strongest hybridizations and the signals remained positive in high stringency wash conditions [24].
  • Altogether, these results suggest that Shc and Grb2-Sos are implicated in ras-dependent Xenopus oocyte maturation induced by insulin/IGF-1; they also indicate that inability of insulin/IGF-1 to activate the Ras-MAPK cascade in vitellogenic oocytes does not result from an insufficient expression level of Shc, Grb2 and Sos [25].

Analytical, diagnostic and therapeutic context of ras

  • We used messenger RNA microinjection of Xenopus eggs to express a dominant inhibitory mutant ras, p21(Asn 17)Ha-ras, in cells competent to respond to inducing factors to examine the role of p21ras in this response [6].
  • The ras gene. Transformer and transducer [26].
  • Sequence analyses of these proteins show them to contain the ras consensus domains involved in GTP binding and metabolism [27].
  • The results imply that blockade of both MEK and JNK-oncogenic ras-p21 interactions may constitute selective synergistic combination chemotherapy against oncogenic ras-induced tumors [28].
  • The expression of the ras protooncogene was investigated in Xenopus laevis, throughout development, by in situ hybridization using a 35S-labelled antisense RNA probe [29].


  1. Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Bischoff, F.R., Ponstingl, H. Nature (1991) [Pubmed]
  2. A novel 110-kDa maternal CAAX box-containing protein from Xenopus is palmitoylated and isoprenylated when expressed in baculovirus. Kloc, M., Reddy, B., Crawford, S., Etkin, L.D. J. Biol. Chem. (1991) [Pubmed]
  3. Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. Leonard, D.M., Shuler, K.R., Poulter, C.J., Eaton, S.R., Sawyer, T.K., Hodges, J.C., Su, T.Z., Scholten, J.D., Gowan, R.C., Sebolt-Leopold, J.S., Doherty, A.M. J. Med. Chem. (1997) [Pubmed]
  4. Inhibition of small G proteins by clostridium sordellii lethal toxin activates cdc2 and MAP kinase in Xenopus oocytes. Rime, H., Talbi, N., Popoff, M.R., Suziedelis, K., Jessus, C., Ozon, R. Dev. Biol. (1998) [Pubmed]
  5. ras proteins can induce meiosis in Xenopus oocytes. Birchmeier, C., Broek, D., Wigler, M. Cell (1985) [Pubmed]
  6. Involvement of p21ras in Xenopus mesoderm induction. Whitman, M., Melton, D.A. Nature (1992) [Pubmed]
  7. Differential regulation of rasGAP and neurofibromatosis gene product activities. Bollag, G., McCormick, F. Nature (1991) [Pubmed]
  8. Inhibition of Ran guanosine triphosphatase-dependent nuclear transport by the matrix protein of vesicular stomatitis virus. Her, L.S., Lund, E., Dahlberg, J.E. Science (1997) [Pubmed]
  9. Induction of mesoderm in Xenopus laevis embryos by translation initiation factor 4E. Klein, P.S., Melton, D.A. Science (1994) [Pubmed]
  10. The ras oncoprotein and M-phase activity. Daar, I., Nebreda, A.R., Yew, N., Sass, P., Paules, R., Santos, E., Wigler, M., Vande Woude, G.F. Science (1991) [Pubmed]
  11. Rapid stimulation of diacylglycerol production in Xenopus oocytes by microinjection of H-ras p21. Lacal, J.C., de la Peña, P., Moscat, J., Garcia-Barreno, P., Anderson, P.S., Aaronson, S.A. Science (1987) [Pubmed]
  12. Regulation of cytoplasmic division of Xenopus embryo by rho p21 and its inhibitory GDP/GTP exchange protein (rho GDI). Kishi, K., Sasaki, T., Kuroda, S., Itoh, T., Takai, Y. J. Cell Biol. (1993) [Pubmed]
  13. Modulation of maturation and ribosomal protein S6 phosphorylation in Xenopus oocytes by microinjection of oncogenic ras protein and protein kinase C. Kamata, T., Kung, H.F. Mol. Cell. Biol. (1990) [Pubmed]
  14. A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase. Itoh, T., Kaibuchi, K., Masuda, T., Yamamoto, T., Matsuura, Y., Maeda, A., Shimizu, K., Takai, Y. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  15. Cytological effects of the microinjection of antibody to ras p21 in early cleavage Xenopus embryos. Miron, M.J., Lanoix, J., Paiement, J. Mol. Reprod. Dev. (1990) [Pubmed]
  16. Ras and p53 intracellular targeting with recombinant single-chain Fv (scFv) fragments: a novel approach for cancer therapy? Cochet, O., Gruel, N., Fridman, W.H., Teillaud, J.L. Cancer Detect. Prev. (1999) [Pubmed]
  17. Activation of smooth muscle alpha-actin promoter in ras-transformed cells by treatments with antimitotic agents: correlation with stimulation of SRF:SRE mediated gene transcription. Kumar, C.C., Kim, J.H., Bushel, P., Armstrong, L., Catino, J.J. J. Biochem. (1995) [Pubmed]
  18. Default neural induction: neuralization of dissociated Xenopus cells is mediated by Ras/MAPK activation. Kuroda, H., Fuentealba, L., Ikeda, A., Reversade, B., De Robertis, E.M. Genes Dev. (2005) [Pubmed]
  19. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Schafer, W.R., Kim, R., Sterne, R., Thorner, J., Kim, S.H., Rine, J. Science (1989) [Pubmed]
  20. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Trahey, M., McCormick, F. Science (1987) [Pubmed]
  21. The antibiotic azatyrosine suppresses progesterone or [Val12]p21 Ha-ras/insulin-like growth factor I-induced germinal vesicle breakdown and tyrosine phosphorylation of Xenopus mitogen-activated protein kinase in oocytes. Campa, M.J., Glickman, J.F., Yamamoto, K., Chang, K.J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  22. Role of phosphatidylinositide metabolism in ras-induced Xenopus oocyte maturation. Pan, B.T., Cooper, G.M. Mol. Cell. Biol. (1990) [Pubmed]
  23. Oncogenic ras stimulates a 96-kDa histone H2b kinase activity in activated Xenopus egg extracts. Correlation with the suppression of p34cdc2 kinase. Chen, C.T., Pan, B.T. J. Biol. Chem. (1994) [Pubmed]
  24. Detection of proto-oncogenes in the genome of the amphibian Xenopus laevis. Moreau, J., Le Guellec, R., Leibovici, M., Couturier, A., Philippe, M., Mechali, M. Oncogene (1989) [Pubmed]
  25. Molecular cloning and characterization of an adaptor protein Shc isoform from Xenopus laevis oocytes. Chesnel, F., Heligon, C., Richard-Parpaillon, L., Boujard, D. Biol. Cell (2003) [Pubmed]
  26. The ras gene. Transformer and transducer. Hanley, M.R., Jackson, T. Nature (1987) [Pubmed]
  27. GSP1 and GSP2, genetic suppressors of the prp20-1 mutant in Saccharomyces cerevisiae: GTP-binding proteins involved in the maintenance of nuclear organization. Belhumeur, P., Lee, A., Tam, R., DiPaolo, T., Fortin, N., Clark, M.W. Mol. Cell. Biol. (1993) [Pubmed]
  28. Induction of oocyte maturation by jun-N-terminal kinase (JNK) on the oncogenic ras-p21 pathway is dependent on the raf-MEK signal transduction pathway. Chie, L., Amar, S., Kung, H.F., Lin, M.C., Chen, H., Chung, D.L., Adler, V., Ronai, Z., Friedman, F.K., Robinson, R.C., Kovac, C., Brandt-Rauf, P.W., Yamaizumi, Z., Michl, J., Pincus, M.R. Cancer Chemother. Pharmacol. (2000) [Pubmed]
  29. Localization of ras proto-oncogene expression during development in Xenopus laevis. Andéol, Y., Méchali, M., Hourdry, J. Mol. Reprod. Dev. (1992) [Pubmed]
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