Abstract
Oncoproteins of the Ras family have been extensively studied because of their implication in human cancer. Their roles have been primarily assigned to the commandment of cell proliferation and suppression of apoptosis, which has also been demonstrated by the involvement of Ras activation in the signal transduction pathways triggered by most cytokine receptors. Nevertheless, the functions of Ras proteins have been extended in the last years by the findings showing that they can also act as promoters or enhancers of apoptosis in various systems and conditions. These considerations have raised the issue as to how the signals delivered by Ras are regulated and translated in terms of cellular responses, suggesting that signal complementation may direct the final fate of cells. As an example, the interleukin-2 receptor system may represent a useful model in which the meaning of Ras signals may be evaluated in terms of interactions with other simultaneous signalling events, since knowledge of the biochemical events triggered by the interaction of interleukin-2 with its cell surface receptor in lymphocytes has allowed the proposal of a complete signalling model arranged in three independent channels, one of which is mediated by Ras.
Similar content being viewed by others
References
Hall A. Ras-related proteins.Curr Opin Cell Biol 1993;376: 265–268.
Chavrier P, Gorvel JP, Bertoglio J. An immunologist's look at the Rho and Rab GTP-binding proteins.Immunol Today 1993;14: 440–444.
Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structures and molecular mechanism.Nature 1991;349: 117–127.
Ridley AJ. Rho-related proteins: actin cytoskeleton and cell cycle.Curr Opin Genet Dev 1995;5: 24–30.
Kayne PS, Sternberg PW. Ras pathways in Caenorhabditis elegans.Curr Opin Genet Dev 1995;5: 38–43.
McCormick F. Ras signaling and NF1.Curr Opin Genet Dev 1995;5: 51–55.
McCormick F. Activators and effectors of ras p21 proteins.Curr Opin Genet Dev 1994;4: 71–76.
Buday M, Egan SE, Viciana PR, Cantrell DA, Downward J. A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated inras activation in T cells.J Biol Chem 1994;269: 9019–9023.
Izquierdo M, Reif K, Cantrell D. The regulation and function of p21ras during T-cell activation and growth.Immunol Today 1995;16: 159–164.
Calés C, Hancock JF, Marshall CJ, Hall A. The cytoplasmic protein GAP is implicated as the target for regulation by theras gene product.Nature 1988;332: 548–551.
Koide H, Satoh T, Nakafuku M, Kaziro Y. GTP-dependent association of Raf-1 with Ha-Ras: identification of Raf as a target downstream of Ras in mammalian cells.Proc Natl Acad Sci USA 1993;90: 8683–8686.
Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase, and MAP kinase.Curr Opin Genet Dev 1994;4: 82–89.
Treisman R. Regulation of transcription by MAP kinase cascades.Curr Opin Cell Biol 1996;8: 205–215.
Marshall MS. Ras target proteins in eukaryotic cells.FASEB J 1995;9: 1311–1318.
McCormick F, Wittinghofer A. Interactions between Ras proteins and their effectors.Curr Opin Biotech 1996;7: 449–456.
Marshall CJ. Ras effectors.Curr Opin Cell Biol 1996;8: 197–204.
Rodriguez-Viciana P, Warne PH, Dhand R,et al. Phosphatidylinositol-3-OH-kinase as a direct target of Ras.Nature 1994;370: 527–532.
Diaz-Meco MT, Lozano J, Municio MM,et al. Evidence for thein vitro andin vivo interaction of Ras with protein kinase C ζ.J Biol Chem 1994;269: 31706–31710.
Shimizu K, Kuroda S, Matsuda S,et al. Synergistic activation by Ras and 14–3–3 protein of a mitogen-activated protein kinase kinase kinase named Ras-dependent extracellular signalregulated kinase kinase stimulator.J Biol Chem 1994;269: 22917–22920.
Hofer F, Fields S, Schneider C, Martin GS. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator.Proc Natl Acad Sci USA 1994;91: 11089–11093.
Han L, Colicelli J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1.Mol Cell Biol 1995;15: 1318–1323.
Russell M, Lange CC, Johnson GL. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1).J Biol Chem 1995;270: 11757–11760.
Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM. KSR, a novel protein kinase required for RAS signal transduction.Cell 1995;83: 879–888.
Maher J, Baker D, Dibb N, Roberts I. Mutant Ras promotes haemopoietic cell proliferation or differentiation in a cells-pecific manner.Leukemia 1996;10: 83–90.
Esteve P, del Peso L, Lacal JC. Induction of apoptosis byrho in NIH3T3 cells requires two complementary signals. Ceramides function as a progression factor for apoptosis.Oncogene 1994;11: 2657–2665.
Satoh T, Nakafufu M, Miyajima A, Kaziro Y. Involvement ofras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4.Proc Natl Acad Sci USA 1991;88: 3314–3318.
Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW. p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein.Proc Natl Acad Sci USA 1992;89: 1587–1591.
Gómez J, Martínez-A C, Fernández B, García A, Rebollo A. Critical role of Ras in the proliferation and prevention of apoptosis mediated by IL-2.J Immunol 1996;157: 2272–2281.
Swan KA, Alberola-Ila J, Gross JA,et al. Involvement of p21ras distinguishes positive and negative selection in thymocytes.EMBO J 1995;14: 276–285.
Graves JD, Downward J, Izquierdo M, Rayter S, Warnw PH, Cantrell DA. The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes.J Immunol 1992;148: 2417–2422.
Izquierdo M, Downward J, Graves JD, Cantrell DA. Role of protein kinase C in T-cell antigen receptor regulation of p21ras: Evidence that two p21ras regulatory pathways coexist in T cells.Mol Cell Biol 1992;12: 3305–3312.
Izquierdo M, Cantrell DA. Protein tyrosine kinases couple the interleukin-2 receptor to p21ras.Eur J Immunol 1993;23: 131–135.
Ravichandran KS, Burakoff SJ. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation.J Biol Chem 1994;269: 1599–1602.
Zhu X, Suen XL, Barbacid M, Bolen JB, Fargnoli J. Interleukin-2-induced tyrosine phosphorylation of Shc proteins correlates with factor-dependent T cell proliferation.J Biol Chem 1994;269: 5518–5522.
Satoh T, Minami Y, Kono T,et al. Interleukin-2 induced activation of Ras requires two domains of interleukin-2 receptor β subunit, the essential region for growth stimulation and Lck-binding domain.J Biol Chem 1992;267: 25423–25427.
Zetterberg A, Larsson O, Wiman KG. What is the restriction point?Curr Opin Cell Biol 1995;7: 835–842.
Graña X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent-kinases, growth suppressor genes and cyclin-dependent kinase inhibitors.Oncogene 1995;11: 211–217.
Harper JW, Elledge SJ. Cdk inhibitors in development and cancer.Curr Opin Genet Dev 1996;6: 56–64.
Powis G. Anticancer drugs acting against signaling pathways.Curr Opin Oncol 1995;7: 554–559.
Avalosse B, Dupont F, Burny A. Gene therapy for cancer.Curr Opin Oncol 1995;7: 94–100.
Liu JJ, Chao JR, Jiang MG, Neg SY, Yan JJY, Yan-Yen HF. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells.Mol Cell Biol 1995;15: 3654–3663.
Winston JT, Coats SR, Wang YZ, Pledger WJ. Regulation of the cell cycle machinery by oncogenic Ras.Oncogene 1996;12: 127–134.
Albanese C, Johnson J, Watanabe G,et al. Transforming p21ras mutants andc-Ets-2 activate the cyclin D1 promoter through distinguishable regions.J Biol Chem 1995;270: 23589–23597.
Arber N, Sutter T, Miyake M,et al. Increased expression of cyclin D1 and the Rb tumor suppressor gene inc-K-ras transformed rat enterocytes.Oncogene 1996;12: 1903–1908.
Galaktionov K, Jessus C, Beach D. Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation.Genes Dev 1995;9: 1046–1058.
Feig LA, Cooper GM. Inhibition of NIH3T3 cell proliferation by a mutant Ras protein with proferential affinity for GDP.Mol Cell Biol 1988;8: 3235–3243.
Kaplan JB. Biological activity of human N-Ras and K-Ras genes containing the Asn 17 dominant negative mutation.Oncol Res 1994;6: 611–615.
Indolfi C, Avvedimento EV, Rapacciuolo A,et al. Inhibition of cellular Ras prevents smooth muscle cell proliferation after vascular injuryin vivo.Nat Med 1995;1: 541–545.
Irani K, Herzlinger S, Finkel T. Ras proteins regulate multiple mitogenic pathway in A10 vascular smooth muscle cells.Biochem Biophys Res Commun 1994;202: 1252–1258.
Satoh T, Nakafuku M, Kaziro Y. Function of Ras as a molecular switch in signal transduction.J Biol Chem 1992;267: 24149–24152.
Wyllie AH, Kerr JF, Currie AR. Cell death in the normal neonatal rat adrenal cortex.J Pathol 1973;111: 255–259.
Wyllie AH. The genetic regulation of apoptosis.Curr Opin Genet Dev 1995; 5: 97–104.
Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation.Nature 1980;284: 555–556.
Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease.Am J Pathol 1990;136: 593–608.
Cohen JJ, Duke RC. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death.J Immunol 1984;132: 38–42.
Sellins KS, Cohen JJ. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes.J Immunol 1987;139: 3199–3206.
Wyllie AH, Arends MJ, Morris RG, Walker SW, Evan G. The apoptosis endonuclease and its regulation.Semin Immunol 1992;4: 389–397.
Nagata S, Golstein P. The Fas death factor.Science 1995;267: 1449–1456.
Korsmeyer SJ. Regulators of cell death.Trends Genet 1995;11: 101–105.
Sakai N, Ogiso Y, Fujita H, Watari H, Koike T, Kuzumaki N. Induction of apoptosis by a dominant negative H-RAS mutant (116Y) in K562 cells.Exp Cell Res 1994;215: 131–136.
Billadeau D, Jelinek DF, Shah N, LeBien TW, Van NB. Introduction of an activated N-ras oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6.Cancer Res 1995;55: 3640–3646.
Kinoshita T, Yokota T, Arai K, Miyajima A. Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors.EMBO J 1995;14: 266–275.
Gardner AM, Johnson GL. Fibroblast growth factor-2 suppression of tumor necrosis factor alpha-mediated apoptosis requires Ras and the activation of mitogen-activated protein kinase.J Biol Chem 1996;271: 14560–14566.
Lin HJ, Eviner V, Prendergast GC, 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.
Nooter K, Boersma AW, Oostrum RG, Burger H, Jochemsen AG, Stoter G. Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line.Br J Cancer 1995;71: 556–561.
Gulbins E, Bissonnette R, Mahboubi A,et al. FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway.Immunity 1995;2: 341–351.
Wilson DJ, Fortner KA, Lynch DH,et al. JNK, but not MAPK, activation is associated with Fas-mediated apoptosis in human T cells.Eur J Immunol 1996;26: 989–994.
Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.Science 1995;270: 1326–1331.
Ferrari G, Greene LA. Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death.Embo J 1994;13: 5922–5928.
Henkemeyer M, Rossi DJ, Holmyard DP,et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein.Nature 1995;377: 695–701.
Wang HG, Millan JA, Cox AD,et al. R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism.J Cell Biol 1995;129: 1103–1114.
Fernandez A, Fosdick LJ, Marin MC,et al. Differential regulation of endogenous endonuclease activation in isolated murine fibroblast nuclei by ras and bcl-2.Oncogene 1995;10: 769–774.
di Jeso B, Ulianich L, Racioppi L,et al. Serum withdrawal induces apoptotic cell death in Ki-ras transformed but not in normal differentiated thyroid cells.Biochem Biophys Res Commun 1995;214: 819–824.
Tanaka N, Ishihara M, Kitagawa M,et al. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1.Cell 1994;77: 829–839.
Fernandez A, Marin MC, McDonnell T, Ananthaswamy HN. Differential sensitivity of normal and Ha-ras-transformed C3H mouse embryo fibroblasts to tumor necrosis factor: induction of bcl-2, c-myc, and manganese superoxide dismutase in resistant cells.Oncogene 1994;9: 2009–2017.
Chen CY, Faller DV. Direction of p21 ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2.Oncogene 1995;11: 1487–1498.
Spaargaren M, Martin GA, McCormick F, Fernandez SM, Bischoff JR. The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner.Biochem J 1994;300: 303–307.
Kinoshita T, Yokota T, Arai K, Miyajima A. Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells.Oncogene 1995;10: 2207–2212.
Fernandez SM, Bischoff JR. Bcl-2 associates with the ras-related protein R-ras p23.Nature 1993;366: 274–275.
Chen CY, Faller DV. Phosphorylation of Bcl-2 protein and association with p21Ras in Ras-induced apoptosis.J Biol Chem 1996;271: 2376–2379.
Chiarugi V, Magnelli L, Cinelli M, Basi G. Apoptosis and the cell cycle.Cell Mol Biol Res 1994;40: 603–612.
Harrington EA, Fanidi A, Evan GI. Oncogenes and cell death.Curr Opin Genet Dev 1994;4: 120–129.
Evan GI, Brown L, Whyte M, Harrington E. Apoptosis and the cell cycle.Curr Opin Cell Biol 1995;7: 825–834.
Meikrantz W, Schlegel R. Apoptosis and the cell cycle.J Cell Biochem 1995;58: 160–174.
White E. p53, guardian of Rb.Nature 1994;371: 21–22.
Hinds PW, Weinberg RA. Tumor suppressor genes.Curr Opin Genet Dev 1994;4: 135–141.
Haffner R, Oren M. Biochemical properties and biological effects of p53.Curr Opin Genet Dev 1995;5: 84–90.
Liebermann DA, Hoffman B, Steinman RA. Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways.Oncogene 1995;11: 199–210.
Hinds PW. The retinoblastoma tumor suppressor protein.Curr Opin Genet Dev 1995;5: 79–83.
Amati B, Land H. Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death.Curr Opin Genet Dev 1994;4: 102–8.
Wu XW, Levine AJ. p53 and E2F-1 cooperate to mediate apoptosis.Proc Natl Acad Sci USA 1994;91: 3602–3606.
Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas.Science 1992;257: 212–214.
Evan GI, Wyllie AH, Gilbert CS,et a. Induction of apoptosis in fibroblasts by c-Myc protein.Cell 1992;69: 119–128.
Minami Y, Nakagawa Y, Kawahara A,et al. Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway.Immunity 1995;2: 89–100.
Miyazaki T, Liu ZJ, Kawahara A,et al. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc and lck cooperate in hematopoietic cell proliferation.Cell 1995;81: 223–231.
Rebollo A, Gómez J, Martínez-A. C. Lessons from immunological, biochemical, and molecular pathways of the activation mediated by IL-2 and IL-4.Adv Immunol 1996;63: 127–196.
Pawson T, Hunter T. Signal transduction and growth control in normal and cancer cells.Curr Opin Genet Dev 1994;4: 1–4.
Gómez J, de la Hera A, Silva A, Pitton C, García A, Rebollo A. Implication of protein kinase C in IL-2 mediated proliferation and apoptosis in a murine T cell clone.Exp Cell Res 1994;213: 178–182.
Rebollo A, Gómez J, Martínez de Aragón A, Lastres P, Silva A, Pérez-Sala D. Apoptosis induced by IL-2 withdrawal is associated with an intracellular acidification.Exp Cell Res 1995;218: 581–585.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by grants from CICYT and Pharmacia-Upjohn.
Rights and permissions
About this article
Cite this article
Gómez, J., Martínez-A, C. & Rebollo, A. Ras-mediated cell proliferation and cell death: some clues from the interleukin-2 receptor system. Apoptosis 1, 175–182 (1996). https://doi.org/10.1007/BF01321100
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01321100