Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Open Life Sciences

formerly Central European Journal of Biology

Editor-in-Chief: Ratajczak, Mariusz

IMPACT FACTOR 2018: 0.504
5-year IMPACT FACTOR: 0.583

CiteScore 2018: 0.63

SCImago Journal Rank (SJR) 2018: 0.266
Source Normalized Impact per Paper (SNIP) 2018: 0.311

ICV 2017: 154.48

Open Access
See all formats and pricing
More options …
Volume 8, Issue 7


Volume 10 (2015)

Ras and Ras mutations in cancer

Satish Rajasekharan
  • Anusandhan Kendra, SASTRA’s Hub for Research & Innovation, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thiagarajan Raman
  • Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613 401, Tamil Nadu, India
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-04-23 | DOI: https://doi.org/10.2478/s11535-013-0158-5


Ras genes are pre-eminent genes that are frequently linked with cancer biology. The functional loss of ras protein caused by various point mutations within the gene, is established as a prognostic factor for the genesis of a constitutively active Ras-MAPK pathway leading to cancer. Ras signaling circuit follows a complex pathway, which connects many signaling molecules and cells. Several strategies have come up for targeting mutant ras proteins for cancer therapy, however, the clinical benefits remain insignificant. Targeting the Ras-MAPK pathway is extremely complicated due its intricate networks involving several upstream and downstream regulators. Blocking oncogenic Ras is still in latent stage and requires alternative approaches to screen the genes involved in Ras transformation. Understanding the mechanism of Ras induced tumorigenesis in diverse cancers and signaling networks will open a path for drug development and other therapeutic approaches.

Keywords: Ras; Cancer; Signaling; MAPK pathway; Oncogene

  • [1] Goodsell D.S., The molecular perspective: the ras oncogene, Oncologist., 1999, 4, 263–264 Google Scholar

  • [2] Harvey J.J., An unidentified virus which causes the rapid production of tumours in mice, Nature, 1964, 204, 1104–1105 http://dx.doi.org/10.1038/2041104b0CrossrefGoogle Scholar

  • [3] Kirsten W.H., Schauf V., McCoy J., Properties of a murine sarcoma virus, Bibl Haematol., 1970, 36, 246–249 Google Scholar

  • [4] Cooper G.M., Cellular transforming genes, Science., 1982, 217, 801–806 http://dx.doi.org/10.1126/science.6285471CrossrefGoogle Scholar

  • [5] 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, 1982, 298, 343–347 http://dx.doi.org/10.1038/298343a0CrossrefGoogle Scholar

  • [6] Parada L.F., Tabin C.J., Shih C., Weinberg R.A., Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene, Nature, 1982, 297, 474–478 http://dx.doi.org/10.1038/297474a0CrossrefGoogle Scholar

  • [7] Wennerberg K., Rossman K.L., Der C.J., The Ras superfamily at a glance, J Cell Sci., 2005, 118, 843–846 http://dx.doi.org/10.1242/jcs.01660CrossrefGoogle Scholar

  • [8] Barbacid M., Ras genes, Annu Rev Biochem., 1987, 56, 779–827 http://dx.doi.org/10.1146/annurev.bi.56.070187.004023CrossrefGoogle Scholar

  • [9] Cohen J.B., Broz S.D., Levinson A.D., Expression of the H-ras proto-oncogene is controlled by alternative splicing, Cell, 1989, 58, 461–472 http://dx.doi.org/10.1016/0092-8674(89)90427-3CrossrefGoogle Scholar

  • [10] Huang M.Y., Cohen J.B., The alternative H-ras protein p19 displays properties of a negative regulator of p21Ras, Oncol Res., 1997, 9, 611–621 Google Scholar

  • [11] Seeburg P.H., Colby W.W., Capon D.J., Goeddel D.V., Levinson A.D., Biological properties of human c-Ha-ras1 genes mutated at codon 12, Nature, 1984, 312, 71–75 http://dx.doi.org/10.1038/312071a0CrossrefGoogle Scholar

  • [12] Smith G., Bounds R., Wolf H., Steele R.J., Carey F.A., Wolf C.R., Activating K-ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours — implications for personalized cancer medicine, Br J. Cancer., 2010, 102, 693–703 http://dx.doi.org/10.1038/sj.bjc.6605534CrossrefGoogle Scholar

  • [13] Johnson L., Mercer K., Greenbaum D., Bronson R.T., Crowley D., Tuveson D.A., et al., Somatic activation of the K-ras oncogene causes early onset lung cancer in mice, Nature, 2001, 410, 1111–1116 http://dx.doi.org/10.1038/35074129CrossrefGoogle Scholar

  • [14] Andreyev H.J, Norman A.R, Cunningham D., Oates J.R., Clarke P.A., Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study, J Natl Cancer Inst., 1998, 90, 675–684 http://dx.doi.org/10.1093/jnci/90.9.675CrossrefGoogle Scholar

  • [15] Naguib A., Wilson C.H., Adams D.J., Arends M.J., Activation of K-RAS by co-mutation of codons 19 and 20 is transforming, J Molecul Sign., 2011, 6, 1–5 http://dx.doi.org/10.1186/1750-2187-6-1CrossrefGoogle Scholar

  • [16] Nishimura S., Sekiya T., Human cancer and cellular oncogenes, Biochem J., 1987, 243, 313–327 Google Scholar

  • [17] Denayer E., Peeters H., Sevenants L., Derbent M., Fryns J.P., Legius E., NRAS mutations in noonan syndrome, Mol Syndromol., 2012, 3, 34–38 Google Scholar

  • [18] Quilliam L.A., Castro A.F., Rogers-Graham K.S., Martin C.B, Der C.J., Bi C., M-ras/R-ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6, J Biol Chem., 1999, 274, 23850–23857 http://dx.doi.org/10.1074/jbc.274.34.23850CrossrefGoogle Scholar

  • [19] Matsumoto K., Asano T., Endo T., Novel small GTPase M-ras participates in reorganization of actin cytoskeleton, Oncogene, 1997, 15, 2409–2417 http://dx.doi.org/10.1038/sj.onc.1201416CrossrefGoogle Scholar

  • [20] Marte B.M., Rodriguez-Viciana P., Wennstrom S., Warne P.H., Downward J., R-ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways, Curr Bio., 1997, 7, 63–70 http://dx.doi.org/10.1016/S0960-9822(06)00028-5CrossrefGoogle Scholar

  • [21] Huff S.Y., Quilliam L.A., Cox A.D., Der C.J., R-ras is regulated by activators and effectors distinct from those that control Ras function, Oncogene, 1997, 14, 133–143 http://dx.doi.org/10.1038/sj.onc.1200815CrossrefGoogle Scholar

  • [22] Takai Y., Sasaki T., Matozaki T., Small GTPbinding proteins, Physiol Rev., 2001, 81, 153–208 Google Scholar

  • [23] Downward J., Ras signalling and apoptosis, Curr Opin Genet Dev., 1998, 8, 49–54 http://dx.doi.org/10.1016/S0959-437X(98)80061-0CrossrefGoogle Scholar

  • [24] Shapiro P., Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy, Crit Rev Clin Lab Sci., 2002, 39, 285–300 http://dx.doi.org/10.1080/10408360290795538CrossrefGoogle Scholar

  • [25] Madrid L.V., Wang C.Y., Guttridge D.C., Schottelius A.J., Baldwin A.S Jr., Mayo M.W., Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappa B, Mol Cell Biol., 2000, 20, 1626–1638 http://dx.doi.org/10.1128/MCB.20.5.1626-1638.2000CrossrefGoogle Scholar

  • [26] Choudhary S., Wang H.C., Pro-apoptotic activity of oncogenic H-ras for histone deacetylase inhibitor to induce apoptosis of human cancer HT29 cells, J Cancer Res Clin Oncol., 2007, 133, 725–739 http://dx.doi.org/10.1007/s00432-007-0213-1CrossrefGoogle Scholar

  • [27] Fecteau K.A., Mei J., Wang H.C., Differential modulation of signaling pathways and apoptosis of ras-transformed cells by a depsipeptide FR901228, J Pharmacol Exp Ther., 2002, 300, 890–899 http://dx.doi.org/10.1124/jpet.300.3.890CrossrefGoogle Scholar

  • [28] Song P., Wei J., Plummer H. 3rd., Wang H.C., Potentiated caspase-3 in Ras-transformed 10T1/2 cells, Biochem Biophys Res Commun., 2004, 322, 557–564 http://dx.doi.org/10.1016/j.bbrc.2004.07.152CrossrefGoogle Scholar

  • [29] Song P., Wei J., Wang H.C., Distinct roles of the ERK pathway in modulating apoptosis of Ras transformed and non-transformed cells induced by anticancer agent FR901228, FEBS Lett., 2005, 579, 90–94 http://dx.doi.org/10.1016/j.febslet.2004.11.050CrossrefGoogle Scholar

  • [30] Kishi T., Hirooka Y., Ito K., Araki S., Konno S., Sunagawa K., Ras-activated caspase 3-dependent apoptosis through MAPK and p53 in RVLM increases sympathetic nerve activity in SHRSP, FASEB J., 2009, 23, 958.8 Google Scholar

  • [31] Tseng Y.S., Tzeng C.C., Chiu A.W., Lin C.H., Won S.J., Wu I.C., et al., Ha-ras overexpression mediated cell apoptosis in the presence of 5-fuorouracil, Exp Cell Res., 2003, 288, 403–414 http://dx.doi.org/10.1016/S0014-4827(03)00225-8CrossrefGoogle Scholar

  • [32] Chen G., Shu J., Stacey D.W., Oncogenic transformation potentiates apoptosis, S-phase arrest and stress-kinase activation by etoposide, Oncogene, 1997, 15, 1643–1651 http://dx.doi.org/10.1038/sj.onc.1201347CrossrefGoogle Scholar

  • [33] Viktorsson K., Heiden T., Molin M., Akusjarvi G., Linder S., Shoshan M.C., Increased apoptosis and increased clonogenic survival of 12V-Hras transformed rat fibroblasts in response to cisplatin, Apoptosis, 2000, 5, 355–367 http://dx.doi.org/10.1023/A:1009639726168CrossrefGoogle Scholar

  • [34] Chang M.Y., Jan M.S., Won S.J., Liu H.S., HarasVal12 oncogene increases susceptibility of NIH/3T3 cells to lovastatin, Biochem Biophy Res Commun., 1998, 248, 62–68 http://dx.doi.org/10.1006/bbrc.1998.8911Google Scholar

  • [35] Puccetti E., Beissert T., Guller S., Li J.E., Hoelzer D., Ottmann O.G., et al., Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic induced apoptosis, Oncogene, 2003, 22, 6900–6908 http://dx.doi.org/10.1038/sj.onc.1206747CrossrefGoogle Scholar

  • [36] Land H., Parada L.F., Weinberg R.A., Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes, Nature, 1983, 304, 596–602 http://dx.doi.org/10.1038/304596a0CrossrefGoogle Scholar

  • [37] Lin H.J., Eviner V., Prendergast G.C., White E., Activated H-ras rescues E1A-induced apoptosis and cooperates with E1A to overcome p53-dependent growth arrest, Mol Cell Biol., 1995, 15, 4536–4544 CrossrefGoogle Scholar

  • [38] Peli J., Schrouter M., Rudaz C., Hahne M, Meyer C., Reichmann E., et al., Oncogenic Ras inhibits Fas ligand-mediated apoptosis by downregulating the expression of Fas, EMBO J., 1999, 18, 1824–1831 http://dx.doi.org/10.1093/emboj/18.7.1824CrossrefGoogle Scholar

  • [39] Santourlidis S., Warskulat U., Florl A.R., Maas S., Pulte T., Fischer J., et al., Hypermethylation of the tumor necrosis factor receptor superfamily 6 (APT1, Fas, CD95/Apo-1) gene promoter at rel nuclear factor kappaB sites in prostatic carcinoma, Mol Carcinog., 2001, 32, 36–43 http://dx.doi.org/10.1002/mc.1062CrossrefGoogle Scholar

  • [40] Gazin C., Wajapeyee N., Gobeil S., Virbasius C.M., Green M.R., An elaborate pathway required for Ras-mediated epigenetic silencing. Nature, 2007, 449, 1073–1077 http://dx.doi.org/10.1038/nature06251CrossrefGoogle Scholar

  • [41] Venables J.P., Aberrant and alternative splicing in cancer, Cancer Res., 2004, 64, 7647–7654 http://dx.doi.org/10.1158/0008-5472.CAN-04-1910CrossrefGoogle Scholar

  • [42] Voice J.K., Klemke R.L., Le A., Jackson J.H., Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility, J Biol Chem., 1999, 274, 17164–17170 http://dx.doi.org/10.1074/jbc.274.24.17164CrossrefGoogle Scholar

  • [43] Liao J., Wolfman J.C., Wolfman A., K-ras regulates the steady-state expression of matrix metalloproteinase 2 in fibroblasts, J Biol Chem., 2003, 278, 31871–31878 http://dx.doi.org/10.1074/jbc.M301931200CrossrefGoogle Scholar

  • [44] Luo F., Ye H., Hamoudi R., Dong G., Zhang W., Patek C.E., et al., K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation, J Pathol., 2010, 220, 542–550 http://dx.doi.org/10.1002/path.2672CrossrefGoogle Scholar

  • [45] Wolfman J.C., Wolfman A., Endogenous c-N-ras provides a steady-state anti-apoptotic signal, J Biol Chem., 2000, 275, 19315–19323 http://dx.doi.org/10.1074/jbc.M000250200CrossrefGoogle Scholar

  • [46] Navarro P., Valverde A.M., Benito M., Lorenzo M., Activated Ha-ras induces apoptosis by association with phosphorylated Bcl-2 in a mitogen-activated protein kinase-independent manner, J Biol Chem., 1999, 274, 18857–18863 http://dx.doi.org/10.1074/jbc.274.27.18857CrossrefGoogle Scholar

  • [47] Khwaja A., Rodriguez-Viciana P., Wennstrom S., Warne P.H., Downward J., Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway, EMBO J., 1997, 16, 2783–2793 http://dx.doi.org/10.1093/emboj/16.10.2783CrossrefGoogle Scholar

  • [48] Kauffmann-Zeh A., Rodriguez-Viciana P., Ulrich E., Gilbert C., Coffer P., Downward J., et al., Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB, Nature, 1997, 385, 544–548 http://dx.doi.org/10.1038/385544a0CrossrefGoogle Scholar

  • [49] Palmero I., Pantoja C., Serrano M., p19ARF links the tumour suppressor p53 to Ras, Nature, 1998, 395, 125–126 http://dx.doi.org/10.1038/25870CrossrefGoogle Scholar

  • [50] Brooks D.G., James R.M., Patek C.E., Williamson J., Arends M.J., Mutant K-ras enhances apoptosis in embryonic stem cells in combination with DNA damage and is associated with increased levels of p19ARF, Oncogene, 2001, 20, 2144–2152 http://dx.doi.org/10.1038/sj.onc.1204309CrossrefGoogle Scholar

  • [51] Capon D.J., Seeburg P.H., McGrath J.P., Hayflick J.S., Edman U., Levinson A.D., et al., Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations, Nature, 1983, 304, 507–513 http://dx.doi.org/10.1038/304507a0CrossrefGoogle Scholar

  • [52] Pells S., Divjak M., Romanowski P., Impey H., Hawkins N.J., Clarke A.R., et al., Developmentally regulated expression of murine K-ras isoforms, Oncogene, 1997, 15, 1781–1786 http://dx.doi.org/10.1038/sj.onc.1201354CrossrefGoogle Scholar

  • [53] Potenza N., Vecchione C., Notte A., De Rienzo A., Rosica A., Bauer L., et al., Replacement of K-ras with H-ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice, EMBO Rep., 2005, 6, 432–437 http://dx.doi.org/10.1038/sj.embor.7400397CrossrefGoogle Scholar

  • [54] Wang Y., You M., Wang Y., Alternative splicing of the K-ras gene in mouse tissues and cell lines, Exp Lung Res., 2001, 27, 255–267 http://dx.doi.org/10.1080/019021401300054028CrossrefGoogle Scholar

  • [55] Plowman S.J., Arends M.J., Brownstein D.G., Luo F., Devenney P.S., Rose L., et al., The K-ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice, Exp Cell Res., 2006, 312, 16–26 http://dx.doi.org/10.1016/j.yexcr.2005.10.004CrossrefGoogle Scholar

  • [56] Frisch S.M., Francis H., Disruption of epithelial cellmatrix interactions induces apoptosis, J Cell Biol., 1994, 124, 619–626 http://dx.doi.org/10.1083/jcb.124.4.619CrossrefGoogle Scholar

  • [57] Rak J., Mitsuhashi Y., Erdos V., Huang S.N., Filmus J., Kerbel R.S., Massive programmed cell death in intestinal epithelial cells induced by three-dimensional growth conditions: suppression by mutant C-H-ras oncogene expression, J Cell Biol., 1995, 131, 1587–1598 http://dx.doi.org/10.1083/jcb.131.6.1587CrossrefGoogle Scholar

  • [58] Krajewska M., Moss S.F., Krajewski S., Song K., Holt P.R., Reed J.C., Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas, Cancer Res., 1996, 56, 2422–2427 Google Scholar

  • [59] Krajewski S., Krajewska M., Reed J.C., Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family, Cancer Res., 1996, 56, 2849–2855 Google Scholar

  • [60] Moss S.F., Agarwal B., Arber N., Guan R.J., Krajewska M., Krajewski S., et al., Increased intestinal Bak expression results in apoptosis, Biochem Biophys Res Commun., 1996, 223, 199–203 http://dx.doi.org/10.1006/bbrc.1996.0869CrossrefGoogle Scholar

  • [61] Rosen K., Rak J., Jin J., Kerbel R.S., Newman M.J., Filmus J., Downregulation of the proapoptotic protein Bak is required for the rasinduced transformation of intestinal epithelial cells, Curr Biol., 1998, 8, 1331–1334 http://dx.doi.org/10.1016/S0960-9822(07)00564-7CrossrefGoogle Scholar

  • [62] Michaelson D., Ahearn I., Bergo M., Young S., Philips M., Membrane trafficking of heterotrimeric G proteins via the endoplasmic reticulum and golgi, Mol Biol Cell., 2002, 13, 3294–3302 http://dx.doi.org/10.1091/mbc.E02-02-0095CrossrefGoogle Scholar

  • [63] Evanko D.S., Thiyagarajan M.M., Wedegaertner P.B., Interaction with Gbetagamma is required for membrane targeting and palmitoylation of Galpha(s) and Galpha(q), J Biol Chem., 2000, 275, 1327–1336 http://dx.doi.org/10.1074/jbc.275.2.1327CrossrefGoogle Scholar

  • [64] Mor A., Philips M.R., Compartmentalized Ras/MAPK signaling, Annu Rev Immunol., 2006, 24, 771–800 http://dx.doi.org/10.1146/annurev.immunol.24.021605.090723CrossrefGoogle Scholar

  • [65] Dai Q., Choy E., Chiu V., Romano J., Slivka S.R., Steitz S.A., et al., Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum, J Biol Chem., 1998, 273, 15030–15034 http://dx.doi.org/10.1074/jbc.273.24.15030CrossrefGoogle Scholar

  • [66] Swarthout J.T., Lobo S., Farh L., Croke M.R., Greentree W.K., Deschenes R.J., et al., DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-ras, J Biol Chem., 2005, 280, 31141–31148 http://dx.doi.org/10.1074/jbc.M504113200CrossrefGoogle Scholar

  • [67] Hancock J.F., Ras proteins: different signals from different locations, Nat Rev Mol Cell Biol., 2003, 4, 373–384 http://dx.doi.org/10.1038/nrm1105CrossrefGoogle Scholar

  • [68] Izaurralde E., Kutay U., von-Kobbe C., Mattaj I.W., Gorlich D., The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus, EMBO J., 1997, 16, 6535–6547 http://dx.doi.org/10.1093/emboj/16.21.6535CrossrefGoogle Scholar

  • [69] Booden M.A., Baker T.L., Solski P.A., Der C.J., Punke S.G., Buss J.E., A non-farnesylated Ha-Ras protein can be palmitoylated and trigger potent differentiation and transformation, J Biol Chem., 1999, 274, 1423–1431 http://dx.doi.org/10.1074/jbc.274.3.1423CrossrefGoogle Scholar

  • [70] Wurzer G., Mosgoeller W., Chabicovsky M., Cerni C., Wesierska-Gade J., Nuclear Ras: unexpected subcellular distribution of oncogenic forms, J Cell Biochem Suppl., 2001, 36, 1–11 http://dx.doi.org/10.1002/jcb.1070CrossrefGoogle Scholar

  • [71] Birchenall-Roberts M.C., Fu T., Kim S.G., Huang Y.K., Dambach M., Resau J.H., et al., K-ras4B proteins are expressed in the nucleolus: Interaction with nucleolin, Biochem Biophys Res Commun., 2006, 348, 540–549 http://dx.doi.org/10.1016/j.bbrc.2006.07.094CrossrefGoogle Scholar

  • [72] Fuentes-Calvo I., Blazquez-Medela A.M., Santos E., Lopez-Novoa J.M., Martinez-Salgado C., Analysis of K-ras nuclear expression in fibroblasts and mesangial cells, PLoS One., 2010, 5, e8703 http://dx.doi.org/10.1371/journal.pone.0008703CrossrefGoogle Scholar

  • [73] Simons K., Ikonen E., Functional rafts in cell membranes, Nature, 1997, 387, 569–572 http://dx.doi.org/10.1038/42408CrossrefGoogle Scholar

  • [74] Eisenberg S., Shvartsman D.E., Ehrlich M., Henis Y.I., Clustering of raft-associated proteins in the external membrane leaflet modulate internal leaflet H-ras diffusion and signaling, Mol Cell Biol., 2006, 26, 7190–7200 http://dx.doi.org/10.1128/MCB.01059-06CrossrefGoogle Scholar

  • [75] Parton R.G., Hancock J.F., Lipid rafts and plasma membrane microorganization: insights from Ras, Trends Cell Biol., 2004, 14, 141–147 http://dx.doi.org/10.1016/j.tcb.2004.02.001CrossrefGoogle Scholar

  • [76] Holbrook J.A., Neu-Yilik G., Hentze M.W., Kulozik A.E., Nonsense-mediated decay approaches the clinic, Nat Genet., 2004, 36, 801–808 http://dx.doi.org/10.1038/ng1403CrossrefGoogle Scholar

  • [77] Wang J., Vock V.M., Li S., Olivas O.R., Wilkinson M.F., A quality control pathway that down-regulates aberrant T-cell receptor (TCR) transcripts by a mechanism requiring UPF2 and translation, J Biol Chem., 2002, 277, 18489–18493 http://dx.doi.org/10.1074/jbc.M111781200CrossrefGoogle Scholar

  • [78] Rehwinkel J., Raes J., Izaurralde E., Nonsensemediated mRNA decay: Target genes and functional diversification of effectors, Trends Biochem Sci., 2006, 31, 639–646 http://dx.doi.org/10.1016/j.tibs.2006.09.005CrossrefGoogle Scholar

  • [79] Barbier J., Dutertre M., Bittencourt D., Sanchez G., Gratadou L., de la Grange P., et al., Regulation of H-ras splice variant expression by cross talk between the p53 and nonsense-mediated mRNA decay pathways, Mol Cell Biol., 2007, 27, 7315–7333 http://dx.doi.org/10.1128/MCB.00272-07CrossrefGoogle Scholar

  • [80] Jung J.W., Cho S.D., Ahn N.S., Yang S.R., Park J.S., Jo E.H., et al., Ras/MAP Kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate, Cancer Lett., 2005, 225, 199–206 http://dx.doi.org/10.1016/j.canlet.2004.11.029CrossrefGoogle Scholar

  • [81] Metrich M., Laurent A.C., Breckler M., Duquesnes N., Hmitou I., Courillau D., et al., Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway, Cell Signal., 2010, 22, 1459–1468 http://dx.doi.org/10.1016/j.cellsig.2010.05.014CrossrefGoogle Scholar

  • [82] Zhou X., Richon V.M., Wang A.H, Yang X.J., Rifkind R.A., Marks P.A., Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras, Proc Natl Acad Sci USA., 2000, 97, 14329–14333 http://dx.doi.org/10.1073/pnas.250494697CrossrefGoogle Scholar

  • [83] Moon A., Kim M.S., Kim T.G., H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: A role for MMP-2 in the H-rasinduced invasive phenotype, Int J Cancer., 2000, 85, 176–181 CrossrefGoogle Scholar

  • [84] Kim M.S., Son M.W., Kim W.B, In Park Y., Moon A., Apicidin, an inhibitor of histone deacetylase, prevents H-ras-induced invasive phenotype, Cancer Lett., 2000, 157, 23–30 http://dx.doi.org/10.1016/S0304-3835(00)00465-1CrossrefGoogle Scholar

  • [85] Lund P., Weisshaupt K., Mikeska T., Jammas D., Chen X., Kuban R.J., et al., Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation, Oncogene, 2006, 25, 4890–4903 http://dx.doi.org/10.1038/sj.onc.1209502CrossrefGoogle Scholar

  • [86] Rouleau J., MacLeod A.R., Szyf M., Regulation of the DNA methyltransferase by the Ras-AP-1 signaling pathway, J Biol Chem., 1995, 270, 1595–1601 http://dx.doi.org/10.1074/jbc.270.4.1595Google Scholar

  • [87] MacLeod A.R., Rouleau J., Szyf M., Regulation of DNA methylation by the Ras signaling pathway, J Biol Chem., 1995, 270, 11327–11337 http://dx.doi.org/10.1074/jbc.270.19.11327CrossrefGoogle Scholar

  • [88] Wainfan E., Poirier L.A., Methyl groups in carcinogenesis: effects on DNA methylation and gene expression, Cancer Res., 1992, 52, 2071–2077 Google Scholar

  • [89] Lu R., Wang X., Chen Z.F., Sun D.F., Tian X.Q., Fang J.Y., Inhibition of the extracellular signal regulated kinase/mitogen-activated protein kinase pathway decrease DNA-methylation in colon cancer cells, J Biol Chem., 2007, 282, 12249–12259 http://dx.doi.org/10.1074/jbc.M608525200CrossrefGoogle Scholar

  • [90] Morgan M.A., Ganser A., Reuter C.W., Targeting the RAS signaling pathway in malignant hematologic diseases, Curr. Drug Targets., 2007, 8, 217–235 http://dx.doi.org/10.2174/138945007779940043CrossrefGoogle Scholar

  • [91] Jin H., Wang X., Ying J., Wong A.H., Cui Y., Srivastava G., et al., Epigenetic silencing of a Ca(2+)-regulated Ras GTPase protein RASAL defines a new mechanism of Ras activation in human cancers, Proc Natl Acad Sci USA., 2007, 104, 12353–12358 http://dx.doi.org/10.1073/pnas.0700153104CrossrefGoogle Scholar

  • [92] Courtois-Cox S., Genther Williams S.M., Reczek E.E., Johnson B.W., McGillicuddy L.T., Johannessen C.M., et al., A negative feedback signaling network underlies oncogene induced senescence, Cancer Cell., 2006, 10, 459–472 http://dx.doi.org/10.1016/j.ccr.2006.10.003CrossrefGoogle Scholar

  • [93] Mo X., Kowenz-Leutz E., Xu H., Leutz A., Ras induces mediator complex exchange on C/EBP beta, Mol Cell., 2004, 13, 241–250 http://dx.doi.org/10.1016/S1097-2765(03)00521-5CrossrefGoogle Scholar

  • [94] Zhu S., Yoon K., Sterneck E., Johnson P.F., Smart R.C., CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling, Proc Natl Acad Sci USA., 2002, 99, 207–212 http://dx.doi.org/10.1073/pnas.012437299CrossrefGoogle Scholar

  • [95] Shuman J.D., Sebastian T., Kaldis P., Copeland T.D., Zhu S., Smart R.C., Cell cycle dependent phosphorylation of C/EBPbeta mediates oncogenic cooperativity between C/EBPbeta and H-rasV12, Mol Cell Biol., 2004, 24, 7380–7391 http://dx.doi.org/10.1128/MCB.24.17.7380-7391.2004CrossrefGoogle Scholar

  • [96] Sebastian T., Johnson P.F., RasV12-mediated down-regulation of CCAAT/enhancer binding protein beta in immortalized fibroblasts requires loss of p19Arf and facilitates bypass of oncogeneinduced senescence, Cancer Res., 2009, 69, 2588–2598 http://dx.doi.org/10.1158/0008-5472.CAN-08-2312CrossrefGoogle Scholar

  • [97] Lee A.C., Fenster B.E., Ito H., Takeda K., Bae N.S., Hirai T., et al., Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species, J Biol Chem., 1999, 274, 7936–7940 http://dx.doi.org/10.1074/jbc.274.12.7936CrossrefGoogle Scholar

  • [98] Minamino T., Yoshida T., Tateno K., Miyauchi H., Zou Y., Toko H., et al., Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis, Circulation, 2003, 108, 2264–2269 http://dx.doi.org/10.1161/01.CIR.0000093274.82929.22CrossrefGoogle Scholar

  • [99] Sun P., Yoshizuka N., New L., Moser B.A., Li Y., Liao R., et al., PRAK is essential for ras-induced senescence and tumor suppression, Cell, 2007, 128, 295–308 http://dx.doi.org/10.1016/j.cell.2006.11.050CrossrefGoogle Scholar

  • [100] Borgdorff V., Lleonart M.E., Bishop C.L., Fessart D., Bergin A.H., Overhoff M.G., et al., Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21Waf1/Cip1, Oncogene, 2010, 29, 2262–2271 http://dx.doi.org/10.1038/onc.2009.497CrossrefGoogle Scholar

  • [101] Cox A.D., Der C.J., Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras, Biochim Biophys Acta., 1997, 1333, F51–71 Google Scholar

  • [102] Reuter C.W., Morgan M.A., Bergmann L., Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood, 2000, 96, 1655–1669 Google Scholar

  • [103] Cortes J., Albitar M., Thomas D., Giles F., Kurzrock R., Thibault A., et al., Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies, Blood, 2003, 101, 1692–1697 http://dx.doi.org/10.1182/blood-2002-07-1973CrossrefGoogle Scholar

  • [104] Alsina M., Fonseca R., Wilson E.F., Belle A.N., Gerbino E., Price-Troska T., et al., Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma, Blood, 2004, 103, 3271–3277 http://dx.doi.org/10.1182/blood-2003-08-2764CrossrefGoogle Scholar

  • [105] Kim E.S., Kies M.S., Fossella F.V., Glisson B.S., Zaknoen S., Statkevich P., et al., Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma, Cancer, 2005, 104, 561–569 http://dx.doi.org/10.1002/cncr.21188CrossrefGoogle Scholar

  • [106] Aoki K., Ohnami S., Yoshida T., Suppression of pancreatic and colon cancer cells by antisense K-ras RNA expression vectors, Methods Mol Med., 2005, 106, 193–204 Google Scholar

  • [107] Chen L.M., Le H.Y., Qin R.Y., Kumar M., Du Z.Y., Xia R.J., et al., Reversal of the phenotype by K-rasval12 silencing mediated by adenovirusdelivered siRNA in human pancreatic cancer cell line Panc-1, World J Gastroenterol., 2005, 11, 831–838 CrossrefGoogle Scholar

  • [108] Fleming J.B., Shen G.L., Holloway S.E., Davis M., Brekken R.A., Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy, Mol. Cancer Res., 2005, 3, 413–423 http://dx.doi.org/10.1158/1541-7786.MCR-04-0206CrossrefGoogle Scholar

  • [109] Rotblat B., Ehrlich M., Haklai R., Kloog Y., The Ras inhibitor farnesyl thio salicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer, Methods Enzymol., 2008, 439, 467–489 http://dx.doi.org/10.1016/S0076-6879(07)00432-6CrossrefGoogle Scholar

  • [110] Barkan B., Starinsky S., Friedman E., Stein R., Kloog Y., The Ras inhibitor farnesyl thio salicylic acid as a potential therapy for neurofibromatosis type 1, Clin Cancer Res., 2006, 12, 5533–5542 http://dx.doi.org/10.1158/1078-0432.CCR-06-0792CrossrefGoogle Scholar

  • [111] Moore M., Hirte H.W., Siu L., Oza A., Hotte S.J., Petrenciuc O., et al., Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors, Ann Oncol., 2005, 16, 1688–1694 http://dx.doi.org/10.1093/annonc/mdi310CrossrefGoogle Scholar

  • [112] Awada A., Hendlisz A., Gil T., Bartholomeus S., Mano M., de Valeriola D., et al., Phase I safety and pharmacokinetics of BAY 43–9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours, Br J Cancer., 2005, 92, 1855–1861 http://dx.doi.org/10.1038/sj.bjc.6602584Google Scholar

  • [113] Piko B., Panitumumab-treatment of metastatic colorectal cancer, Magy Onkol., 2009, 53, 135–142 http://dx.doi.org/10.1556/MOnkol.53.2009.2.5CrossrefGoogle Scholar

  • [114] Martinelli E., De Palma R., Orditura M., De Vita F., Ciardiello F., Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy, Clin Exp Immunol., 2009, 158, 1–9 http://dx.doi.org/10.1111/j.1365-2249.2009.03992.xCrossrefGoogle Scholar

  • [115] Heinemann V., Stintzing S., Kirchner T., Boeck S., Jung A., Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR, Cancer Treatment Reviews., 2009, 35, 262–271 http://dx.doi.org/10.1016/j.ctrv.2008.11.005CrossrefGoogle Scholar

  • [116] Paliga A., Onerheim R., Gologan A., Chong G., Spatz A., Niazi T., et al., EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors? Bri J Cancer., 2012, 107, 1864–1868 http://dx.doi.org/10.1038/bjc.2012.479CrossrefGoogle Scholar

  • [117] Gysin S., Salt M., Young A., McCormick F., Therapeutic Strategies for Targeting Ras Proteins, Gen Canc., 2011, 2, 359–372 http://dx.doi.org/10.1177/1947601911412376CrossrefGoogle Scholar

  • [118] Wu P., Liu T., Hu Y., PI3K inhibitors for cancer therapy: what has been achieved so far? Curr Med Chem., 2009, 16, 916–930 http://dx.doi.org/10.2174/092986709787581905CrossrefGoogle Scholar

  • [119] Bennett B.L., Sasaki D.T., Murray B.W., O’Leary E.C., Sakata S.T., Xu W., et al., SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase, Proc Natl Acad Sci USA., 2001, 98, 13681–13686 http://dx.doi.org/10.1073/pnas.251194298CrossrefGoogle Scholar

  • [120] Akalin G., Incesu Z., The effects of carvacrol on apoptosis of H-ras and N-ras transformed cell lines, Turk J Pharm Sci., 2011, 8, 105–116 Google Scholar

  • [121] Joachim R., Weiru W., Guowei F., Inhibitors of Infamous Ras Oncogene Uncovered, American Society for Cell Biology’s 51st Annual Meeting in Denver, State of Colorado, 2011 Google Scholar

  • [122] Bos J.L., Ras oncogenes in human cancer: a review, Cancer Res., 1989, 49, 4682–4689 Google Scholar

  • [123] Parsons B.L., Culp S.J., Manjanatha M.G., Heflich R.H., Occurrence of H-ras codon 61 CAA to AAA mutation during mouse liver tumor progression, Carcinogenesis, 2002, 23, 943–948 http://dx.doi.org/10.1093/carcin/23.6.943CrossrefGoogle Scholar

  • [124] Imamura Y., Morikawa T., Liao X., Lochhead P., Kuchiba A., Yamauchi M., et al., Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers, Clin Cancer Res., 2012, 18, 4753–4763 http://dx.doi.org/10.1158/1078-0432.CCR-11-3210CrossrefGoogle Scholar

  • [125] Edkins S., O’Meara S., Parker A., Stevens C., Reis M., Jones S., et al., Recurrent KRAS codon 146 mutations in human colorectal cancer, Cancer Biol Ther., 2006, 5, 928–932 http://dx.doi.org/10.4161/cbt.5.8.3251CrossrefGoogle Scholar

  • [126] Omholt K., Karsberg S., Platz A., Kanter L., Ringborg U., Hansson J., Screening of N-ras codon 61 mutations in paired primary and metastatic cutaneous melanomas: mutations occur early and persist throughout tumor progression, Clin Cancer Res., 2002, 8, 3468–3474 Google Scholar

  • [127] Irahara N., Baba Y., Nosho K., Shima K., Yan L., Dias-Santagata D., et al., NRAS mutations are rare in colorectal cancer, Diagn Mol Pathol., 2010, 19, 157–163 http://dx.doi.org/10.1097/PDM.0b013e3181c93fd1CrossrefGoogle Scholar

  • [128] Quilliam L.A., Castro A.F., Rogers-Graham K.S., Martin C.B., Der C.J., Bi C., et al., M-ras/R-ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6, J Biol Chem., 1999, 274, 23850–23857 http://dx.doi.org/10.1074/jbc.274.34.23850CrossrefGoogle Scholar

  • [129] Saez R., Chan A.M., Miki T., Aaronson S.A., Oncogenic activation of human R-ras by point mutations analogous to those of prototype H-ras oncogenes, Oncogene, 1994, 9, 2977–2982 Google Scholar

  • [130] Desjardins A., Reardon D.A., Peters K.B., Threatt S, Coan A.D, Herndon J.E., et al., A phase I trial of the farnesyl transferase inhibitor, SCH 66336, with temozolomide for patients with malignant glioma, J Neurooncol., 2011, 105, 601–606 http://dx.doi.org/10.1007/s11060-011-0627-0CrossrefGoogle Scholar

  • [131] Theodore C., Geoffrois L., Vermorken J.B., Caponigro F., Fiedler W., Chollet P., et al., Multicentre EORTC study 16997: Feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers, Eur J Cancer., 2005, 41, 1150–1157 http://dx.doi.org/10.1016/j.ejca.2005.02.015CrossrefGoogle Scholar

  • [132] Winquist E., Moore M.J., Chi K.N., Ernst D.S., Hirte H., North S., et al., A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer, Urol Oncol., 2005, 23, 143–149 http://dx.doi.org/10.1016/j.urolonc.2004.12.012CrossrefGoogle Scholar

  • [133] Khuri F.R., Glisson B.S., Kim E.S., Statkevich P., Thall P.F, Meyers M.L., et al., Phase I study of the farnesyl transferase inhibitor lonafarnib with paclitaxel in solid tumors, Clin Cancer Res., 2004, 10, 2968–2976 http://dx.doi.org/10.1158/1078-0432.CCR-03-0412CrossrefGoogle Scholar

  • [134] Kim E.S., Kies M.S., Fossella F.V., Glisson B.S., Zaknoen S., Statkevich P., et al., Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma, Cancer, 2005, 104, 561–569 http://dx.doi.org/10.1002/cncr.21188CrossrefGoogle Scholar

  • [135] Johnston S.R., Hickish T., Ellis P., Houston S., Kelland L., Dowsett M., et al., Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer, J Clin Oncol., 2003, 21, 2492–2499 http://dx.doi.org/10.1200/JCO.2003.10.064CrossrefGoogle Scholar

  • [136] Adjei A.A., Mauer A., Bruzek L., Marks R.S., Hillman S., Geyer S., et al., Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer, J Clin Oncol., 2003, 21, 1760–1766 http://dx.doi.org/10.1200/JCO.2003.09.075CrossrefGoogle Scholar

  • [137] Crul M., Klerk G.J.D., Swart M., Veer L.J.V., Jong D.D., Boerrigter L., et al., Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer, J Clin Onco., 2002, 20, 2726–2735 http://dx.doi.org/10.1200/JCO.2002.09.116CrossrefGoogle Scholar

  • [138] Heymach J.V., Johnson D.H., Khuri F.R., Safran H, Schlabach L.L., Yunus F., et al., Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer, Ann Oncol., 2004, 15, 1187–1193 http://dx.doi.org/10.1093/annonc/mdh315CrossrefGoogle Scholar

  • [139] Rao S., Cunningham D., Gramont D.A., Scheithauer W., Smakal M., et al., Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer, J Clin Oncol., 2004, 22, 3950–3957 http://dx.doi.org/10.1200/JCO.2004.10.037CrossrefGoogle Scholar

  • [140] Van Cutsem E., van de Velde H., Karasek P., Oettle H., Vervenne W.L., Szawlowski A., et al., Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer, J Clin Oncol., 2004, 22, 1430–1438 http://dx.doi.org/10.1200/JCO.2004.10.112CrossrefGoogle Scholar

  • [141] Cortes J., Faderl S., Estey E., Kurzrock R., Thomas D., Beran M., et al., Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes, J Clin Oncol., 2005, 23, 2805–2812 http://dx.doi.org/10.1200/JCO.2005.09.005CrossrefGoogle Scholar

  • [142] Ryan D.P, Eder J.P Jr, Puchlaski T, Seiden M.V, Lynch T.J, Fuchs C.S., et al., Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors, Clin Cancer Res., 2004, 10, 2222–2230 http://dx.doi.org/10.1158/1078-0432.CCR-0980-3Google Scholar

  • [143] Bailey H.H., Alberti D.B., Thomas J.P., Mulkerin D.L., Binger K.A., Gottardis M.M., et al., Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors, Clin Cancer Res., 2007, 15, 3623–3629 http://dx.doi.org/10.1158/1078-0432.CCR-07-0158Google Scholar

  • [144] Hahn S.M., Bernhard E.J., Regine W., Mohiuddin M., Haller D.G., Stevenson J.P., et al., A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer, Clin Cancer Res., 2002, 8, 1065–1072 Google Scholar

  • [145] Giaccone G., Herbst R.S., Manegold C., Scagliotti G., Rosell R., Miller V., et al., Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1, J. Clin. Oncol., 2004, 22, 777–784 http://dx.doi.org/10.1200/JCO.2004.08.001Google Scholar

  • [146] Perez-Soler R., Chachoua A., Hammond L.A., Rowinsky E.K., Huberman M., Karp D., et al., Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer, J. Clin Oncol., 2004, 22, 3238–3247 http://dx.doi.org/10.1200/JCO.2004.11.057CrossrefGoogle Scholar

  • [147] Herbst R.S., Prager D., Hermann R., Fehrenbacher L., Johnson B.E., Sandler A., et al., TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer, J Clin Oncol., 2005, 23, 5892–5899 http://dx.doi.org/10.1200/JCO.2005.02.840Google Scholar

  • [148] Herbst R.S., Johnson D.H., Mininberg E., Carbone D.P., Henderson T., Kim E.S., et al., Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer, J Clin Oncol., 2005, 23, 2544–2555 http://dx.doi.org/10.1200/JCO.2005.02.477CrossrefGoogle Scholar

About the article

Published Online: 2013-04-23

Published in Print: 2013-07-01

Citation Information: Open Life Sciences, Volume 8, Issue 7, Pages 609–624, ISSN (Online) 2391-5412, DOI: https://doi.org/10.2478/s11535-013-0158-5.

Export Citation

© 2013 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Comments (0)

Please log in or register to comment.
Log in