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The dark side of Ras: regulation of apoptosis

Oncogene volume 22, pages 8999–9006 (2003)Cite this article

Abstract

Mutational activation of Ras promotes oncogenesis by disrupting a multitude of normal cellular processes. Perhaps, best characterized and understood are the mechanisms by which oncogenic Ras promotes deregulated cell cycle progression and uncontrolled cellular proliferation. However, it is now clear that oncogenic Ras can also deregulate processes that control apoptosis. In light of the diversity of downstream effector targets known to facilitate Ras function, it is perhaps not surprising that Ras regulation of cell survival is complex, involving the balance and interplay of multiple signaling networks. While our understanding of these events is still far from complete, and is complicated by cell type and signaling context differences, several important mechanisms have begun to emerge. We review the role and mechanism of specific effectors in regulating the antiapoptotic (Raf, phosphatidylinositol 3-kinase and Tiam1) and apoptotic (Nore1 and RASSF1) actions of oncogenic Ras, and discuss the possibility that the effector actions of p120RasGAP make a significant contribution to Ras regulation of apoptotic events.

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References

  • Balachandran S, Porosnicu M and Barber GN . (2001). J. Virol., 75, 3474–3479.

  • Barradas M, Monjas A, Diaz-Meco MT, Serrano M and Moscat J . (1999). EMBO J., 18, 6362–6369.

  • Bazarov AV, Adachi S, Li SF, Mateyak MK, Wei S and Sedivy JM . (2001). Cancer Res., 61, 1178–1186.

  • Blume-Jensen P, Janknecht R and Hunter T . (1998). Curr. Biol., 8, 779–782.

  • Bonni A, Brunet A, West AE, Datta SR, Takasu MA and Greenberg ME . (1999). Science, 286, 1358–1362.

  • Chen Z, Sun J, Pradines A, Favre G, Adnane J and Sebti SM . (2000). J. Biol. Chem., 275, 17974–17978.

  • Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O’Hagan R, Pantginis J, Zhou H, Horner II JW, Cordon-Cardo C, Yancopoulos GD and DePinho RA . (1999). Nature, 400, 468–472.

  • Clarke P, Meintzer SM, Gibson S, Widmann C, Garrington TP, Johnson GL and Tyler KL . (2000). J. Virol., 74, 8135–8139.

  • Coffey MC, Strong JE, Forsyth PA and Lee PW . (1998). Science, 282, 1332–1334.

  • Coniglio SJ, Jou TS and Symons M . (2001). J. Biol. Chem., 276, 28113–28120.

  • Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ, Marinkovich MP, Tao S, Lin Q, Kubo Y and Khavari PA . (2003). Nature, 421, 639–643.

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S and Pfeifer GP . (2000). Nat. Genet., 25, 315–319.

  • Datta SR, Brunet A and Greenberg ME . (1999). Genes. Dev., 13, 2905–2927.

  • DeChant AK, Dee K and Weyman CM . (2002). Oncogene, 21, 5268–5279.

  • Denis GV, Yu Q, Ma P, Deeds L, Faller DV and Chen CY . (2003). J. Biol. Chem., 278, 5775–5785.

  • Downward J . (1998). Curr. Opin. Genet. Dev., 8, 49–54.

  • Du K and Montminy M . (1998). J. Biol. Chem., 273, 32377–32379.

  • Du W and Prendergast GC . (1999). Cancer Res., 59, 5492–5496.

  • Ehrhardt GR, Leslie KB, Lee F, Wieler JS and Schrader JW . (1999). Blood, 94, 2433–2444.

  • Erhardt P, Schremser EJ and Cooper GM . (1999). Mol. Cell. Biol., 19, 5308–5315.

  • Essmann F, Wieder T, Otto A, Muller EC, Dorken B and Daniel PT . (2000). Biochem. J., 346 (Part 3), 777–783.

  • Fang X, Yu S, Eder A, Mao M, Bast Jr RC, Boyd D and Mills GB . (1999). Oncogene, 18, 6635–6640.

  • Feig LA and Buchsbaum RJ . (2002). Curr. Biol., 12, R259–R261.

  • Fiordalisi JJ, Holly SP, Johnson II RL, Parise LV and Cox AD . (2002). J. Biol. Chem., 277, 10813–10823.

  • Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A and Varmus HE . (2001). Genes Dev., 15, 3249–3262.

  • Frisch SM and Francis H . (1994). J. Cell. Biol., 124, 619–626.

  • Fritz G and Kaina B . (2000). Biochem. Biophys. Res. Commun., 268, 784–789.

  • Fritz G and Kaina B . (2001). J. Biol. Chem., 276, 3115–3122.

  • Gigoux V, L’Hoste S, Raynaud F, Camonis J and Garbay C . (2002). J. Biol. Chem., 277, 23742–23746.

  • Gire V, Marshall C and Wynford-Thomas D . (2000). Oncogene, 19, 2269–2276.

  • Grad JM, Zeng XR and Boise LH . (2000). Curr. Opin. Oncol., 12, 543–549.

  • Guan KL, Figueroa C, Brtva TR, Zhu T, Taylor J, Barber TD and Vojtek AB . (2000). J. Biol. Chem., 275, 27354–27359.

  • Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T and Pawson T . (1995). Nature, 377, 695–701.

  • Hueber AO and Evan GI . (1998). Trends Genet., 14, 364–367.

  • Huser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S, Sun XM, Brown J, Marais R and Pritchard C . (2001). EMBO J., 20, 1940–1951.

  • Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T and Goldschmidt-Clermont PJ . (1997). Science, 275, 1649–1652.

  • Joneson T and Bar-Sagi D . (1999). Mol. Cell. Biol., 19, 5892–5901.

  • Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J and Evan G . (1997). Nature, 385, 544–548.

  • Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN and Hay N . (1997). Genes Dev., 11, 701–713.

  • Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B and Avruch J . (2002). Curr. Biol., 12, 253–265.

  • Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH and Downward J . (1997). EMBO J., 16, 2783–2793.

  • Kinoshita T, Shirouzu M, Kamiya A, Hashimoto K, Yokoyama S and Miyajima A . (1997). Oncogene, 15, 619–627.

  • Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG and Der CJ . (2002). Nat. Cell. Biol., 4, 621–625.

  • Le Gall M, Chambard JC, Breittmayer JP, Grall D, Pouyssegur J and Van Obberghen-Schilling E . (2000). Mol. Cell. Biol., 11, 1103–1112.

  • Leblanc V, Delumeau I and Tocque B . (1999). Oncogene, 18, 4884–4889.

  • Lee KK, Ohyama T, Yajima N, Tsubuki S and Yonehara S . (2001). J. Biol. Chem., 276, 19276–19285.

  • Liu A, Cerniglia GJ, Bernhard EJ and Prendergast GC . (2001). Proc. Natl. Acad. Sci. USA, 98, 6192–6197.

  • Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F and Collard JG . (2002). Nature, 417, 867–871.

  • Marte BM and Downward J . (1997). Trends Biochem. Sci., 22, 355–358.

  • Mayo MW and Baldwin AS . (2000). Biochim. Biophys. Acta, 1470, M55–M62.

  • Mayo MW, Wang CY, Cogswell PC, Rogers-Graham KS, Lowe SW, Der CJ and Baldwin Jr AS . (1997). Science, 278, 1812–1815.

  • Mazzoni IE, Said FA, Aloyz R, Miller FD and Kaplan D . (1999). J. Neurosci., 19, 9716–9727.

  • McFall A, Ulku A, Lambert QT, Kusa A, Rogers-Graham K and Der CJ . (2001). Mol. Cell. Biol., 21, 5488–5499.

  • Na S, Chuang TH, Cunningham A, Turi TG, Hanke JH, Bokoch GM and Danley DE . (1996). J. Biol. Chem., 271, 11209–11213.

  • Nalca A, Qiu SG, El-Guendy N, Krishnan S and Rangnekar VM . (1999). J. Biol. Chem., 274, 29976–29983.

  • Navarro P, Valverde AM, Benito M and Lorenzo M . (1999). J. Biol. Chem., 274, 18857–18863.

  • Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP and Avruch J . (2002). Oncogene, 21, 1381–1390.

  • Osada M, Tolkacheva T, Li W, Chan TO, Tsichlis PN, Saez R, Kimmelman AC and Chan AM . (1999). Mol. Cell. Biol., 19, 6333–6344.

  • Pfeifer GP, Yoon JH, Liu L, Tommasi S, Wilczynski SP and Dammann R . (2002). Biol. Chem., 383, 907–914.

  • Prendergast GC . (2001). Nat. Rev. Cancer, 1, 162–168.

  • Rak J, Mitsuhashi Y, Erdos V, Huang SN, Filmus J and Kerbel RS . (1995). J. Cell. Biol., 131, 1587–1598.

  • Reusch HP, Zimmermann S, Schaefer M, Paul M and Moelling K . (2001). J. Biol. Chem., 276, 33630–33637.

  • Reuther GW and Der CJ . (2000). Curr. Opin. Cell. Biol., 12, 157–165.

  • Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M and McCormick F . (2000). Cell, 103, 321–330.

  • Romashkova JA and Makarov SS . (1999). Nature, 401, 86–90.

  • Rong R, He Q, Liu Y, Sheikh MS and Huang Y . (2002). Oncogene, 21, 1062–1070.

  • Rosen K, Rak J, Jin J, Kerbel RS, Newman MJ and Filmus J . (1998). Curr. Biol., 8, 1331–1334.

  • Rosen K, Rak J, Leung T, Dean NM, Kerbel RS and Filmus J . (2000). J. Cell. Biol., 149, 447–456.

  • Rusyn EV, Reynolds ER, Shao H, Grana TM, Chan TO, Andres DA and Cox AD . (2000). Oncogene, 19, 4685–4694.

  • Rytomaa M, Lehmann K and Downward J . (2000). Oncogene, 19, 4461–4468.

  • Sears R, Nuckolls F, Haura E, Taya Y, Tamai K and Nevins JR . (2000). Genes Dev., 14, 2501–2514.

  • Shields JM, Pruitt K, McFall A, Shaub A and Der CJ . (2000). Trends Cell. Biol., 10, 147–154.

  • Sulciner DJ, Irani K, Yu ZX, Ferrans VJ, Goldschmidt-Clermont P and Finkel T . (1996). Mol. Cell. Biol., 16, 7115–7121.

  • Suzuki J, Kaziro Y and Koide H . (1998). FEBS Lett., 437, 112–116.

  • Tan Y, Ruan H, Demeter MR and Comb MJ . (1999). J. Biol. Chem., 274, 34859–34867.

  • Terada K, Kaziro Y and Satoh T . (2000). Biochem. Biophys. Res. Commun., 267, 449–455.

  • Tocque B, Delumeau I, Parker F, Maurier F, Multon MC and Schweighoffer F . (1997). Cell Signal., 9, 153–158.

  • Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y and Rozakis-Adcock M . (2001). J. Biol. Chem., 276, 13087–13095.

  • Tsuchida T, Kijima H, Hori S, Oshika Y, Tokunaga T, Kawai K, Yamazaki H, Ueyama Y, Scanlon KJ, Tamaoki N and Nakamura M . (2000). Cancer Gene Ther., 7, 373–383.

  • Tsuneoka M and Mekada E . (2000). Oncogene, 19, 115–123.

  • Tu S and Cerione RA . (2001). J. Biol. Chem., 276, 19656–19663.

  • Tu SS, Wu WJ, Yang W, Nolbant P, Hahn K and Cerione RA . (2002). Biochemistry, 41, 12350–12358.

  • von Gise A, Lorenz P, Wellbrock C, Hemmings B, Berberich-Siebelt F, Rapp UR and Troppmair J . (2001). Mol. Cell. Biol., 21, 2324–2336.

  • Vos MD, Ellis CA, Bell A, Birrer MJ and Clark GJ . (2000). J. Biol. Chem., 275, 35669–35672.

  • Wang HG, Millan JA, Cox AD, Der CJ, Rapp UR, Beck T, Zha H and Reed JC . (1995). J. Cell. Biol., 129, 1103–1114.

  • Wang HG, Rapp UR and Reed JC . (1996). Cell, 87, 629–638.

  • Wen LP, Madani K, Martin GA and Rosen GD . (1998). Cell. Death Differ., 5, 729–734.

  • Widmann C, Gibson S and Johnson GL . (1998). J. Biol. Chem., 273, 7141–7147.

  • Wolfman JC, Palmby T, Der CJ and Wolfman A . (2002). Mol. Cell. Biol., 22, 1589–1606.

  • Xue L, Murray JH and Tolkovsky AM . (2000). J. Biol. Chem., 275, 8817–8824.

  • Yang JY and Widmann C . (2001). Mol. Cell. Biol., 21, 5346–5358.

  • Yang JY and Widmann C . (2002). J. Biol. Chem., 277, 14641–14646.

  • Zimmermann S and Moelling K . (1999). Science, 286, 1741–1744.

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Acknowledgements

We apologize for not being able to cite original work of many colleagues due to space constraints. Our studies were supported by grants from the National Institutes of Health (CA42978, CA69577 and CA67771), and from the Lustgarten Foundation for Pancreatic Cancer Research (LF-056).

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  1. Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    Adrienne D Cox & Channing J Der

  2. Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    Adrienne D Cox

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Cox, A., Der, C. The dark side of Ras: regulation of apoptosis. Oncogene 22, 8999–9006 (2003). https://doi.org/10.1038/sj.onc.1207111

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