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Ras GTPases Are Both Regulators and Effectors of Redox Agents

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Ras Signaling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1120))

Abstract

Redox agents have been historically considered pathological agents which can react with and damage many biological macromolecules including DNA, proteins, and lipids. However, a growing number of reports have suggested that mammalian cells can rapidly respond to ligand stimulation with a change in intracellular ROS thus indicating that the production of intracellular redox agents is tightly regulated and that they serve as intracellular signaling molecules being involved in a variety of cell signaling pathways. Numerous observations have suggested that some members of the Ras GTPase superfamily appear to regulate the production of redox agents and that oxidants can function as effector molecules for the small GTPases, thus contributing to their overall biological function. In addition, many of the Ras superfamily small GTPases have been shown to be redox sensitive, thanks to the presence of redox-sensitive sequences in their primary structure. The action of redox agents on these redox-sensitive GTPases is similar to that of guanine nucleotide exchange factors in that they perturb GTPase nucleotide-binding interactions that result in the enhancement of the guanine nucleotide exchange of small GTPases.

Thus, Ras GTPases may act both as upstream regulators and downstream effectors of redox agents.

Here we overview current understanding concerning the interplay between Ras GTPases and redox agents, also taking into account pathological implications of misregulation of this cross talk and highlighting the potentiality of these cellular pathways as new therapeutical targets for different pathologies.

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References

  1. Herrmann C (2003) Ras-effector interactions: after one decade. Curr Opin Struct Biol 13:122–129

    Article  PubMed  CAS  Google Scholar 

  2. Heo J (2008) Redox regulation of Ran GTPase. Biochem Biophys Res Commun 376:568–572

    Article  PubMed  CAS  Google Scholar 

  3. Heo J, Campbell SL (2004) Mechanism of p21Ras S-nitrosylation and kinetics of nitric oxide-mediated guanine nucleotide exchange. Biochemistry 43:2314–2322

    Article  PubMed  CAS  Google Scholar 

  4. Heo J, Campbell SL (2005) Mechanism of redox-mediated guanine nucleotide exchange on redox-active Rho GTPases. J Biol Chem 280:31003–31010

    Article  PubMed  CAS  Google Scholar 

  5. Heo J (2011) Redox control of GTPases: from molecular mechanisms to functional significance in health and disease. Antioxid Redox Signal 15:689–724

    Article  Google Scholar 

  6. Davis MF, Vigil D, Campbell SL (2011) Regulation of Ras proteins by reactive nitrogen species. Free Rad Biol Med 51:565–575

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Mitchell L, Hobbs GA, Aghajanian A et al (2013) Redox regulation of Ras and Rho GTPases: mechanism and function. Antioxid Redox Signal 20:250–258

    Article  CAS  Google Scholar 

  8. Sundaresan M, Yu ZX, Ferrans VJ et al (1995) Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270:296–299

    Article  PubMed  CAS  Google Scholar 

  9. Bae YS, Kang SW, Seo MS et al (1997) Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272:217–221

    Article  PubMed  CAS  Google Scholar 

  10. Leto TL, Geiszt M (2006) Role of Nox family NADPH oxidases in host defense. Antioxid Redox Signal 8:1549–1561

    Article  PubMed  CAS  Google Scholar 

  11. Kheradmand F, Werner E, Tremble P et al (1998) Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 280:898–902

    Article  PubMed  CAS  Google Scholar 

  12. Werner E, Werb Z (2002) Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J Cell Biol 158:357–368

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Chiarugi P, Pani G, Giannoni E et al (2003) Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161:933–944

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14:495–502

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Fortuño A, San José G, Moreno MU et al (2005) Oxidative stress and vascular remodelling. Exp Physiol 90:457–462

    Article  PubMed  CAS  Google Scholar 

  16. Miller AA, Drummond GR, Sobey CG (2006) Reactive oxygen species in the cerebral circulation: are they all bad? Antioxid Redox Signal 8:1113–1120

    Article  PubMed  CAS  Google Scholar 

  17. Valko M, Leibfritz D, Moncol J et al (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  PubMed  CAS  Google Scholar 

  18. Finkel T (2006) Intracellular redox regulation by the family of small GTPases. Antioxid Redox Signal 8:1857–1863

    Article  PubMed  CAS  Google Scholar 

  19. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100:328–335

    Article  PubMed  CAS  Google Scholar 

  21. Iadecola C, Park L, Capone C (2009) Threats to the mind: aging, amyloid, and hypertension. Stroke 40:S40–S44

    Article  PubMed  PubMed Central  Google Scholar 

  22. Faraci FM, Didion SP (2004) Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol 24:1367–1373

    Article  PubMed  CAS  Google Scholar 

  23. Blough NV, Zafiriou OC (1985) Reaction of superoxide with nitric oxide to form peroxynitrite in alkaline aqueous solution. Inorg Chem 24:3502–3504

    Article  CAS  Google Scholar 

  24. Hill BG, Dranka BP, Bailey SM et al (2010) What part of NO don’t you understand? Some answers to the cardinal questions in nitric oxide biology. J Biol Chem 285:19699–19704

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Pryor WA, Lightsey JW (1981) Mechanisms of nitrogen dioxide reactions: initiation of lipid peroxidation and the production of nitrous acid. Science 214:435–437

    Article  PubMed  CAS  Google Scholar 

  26. Thomas HV, Mueller PK, Lyman RL (1968) Lipoperoxidation of lung lipids in rats exposed to nitrogen dioxide. Science 159:532–534

    Article  PubMed  CAS  Google Scholar 

  27. Misiaszek R, Crean C, Geacintov NE et al (2005) Combination of nitrogen dioxide radicals with 8-oxo-7,8-dihydroguanine and guanine radicals in DNA: oxidation and nitration end-products. J Am Chem Soc 127:2191–2200

    Article  PubMed  CAS  Google Scholar 

  28. Niles JC, Wishnok JS, Tannenbaum SR (2006) Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine: structures and mechanisms of product formation. Nitric Oxide 14:109–121

    Article  PubMed  CAS  Google Scholar 

  29. Bian K, Gao Z, Weisbrodt N et al (2003) The nature of heme/iron-induced protein tyrosine nitration. Proc Natl Acad Sci U S A 100:5712–5717

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Thomas DD, Espey MG, Vitek MP et al (2002) Protein nitration is mediated by heme and free metals through Fenton-type chemistry: and alternative to the NO/O2-reaction. Proc Natl Acad Sci U S A 99:12691–12696

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Bonini MG, Fernandes DC, Augusto O (2004) Albumin oxidation to diverse radicals by the peroxidase activity of Cu, Zn-superoxide dismutase in the presence of bicarbonate or nitrite: diffusible radicals produce cysteinyl and solvent-exposed and -unexposed tyrosyl radicals. Biochemistry 43:344–351

    Article  PubMed  CAS  Google Scholar 

  32. Jiang H, Kruger N, Lahiri DR et al (1999) Nitrogen dioxide induces cis–trans-isomerization of arachidonic acid within cellular phospholipids. Detection of trans-arachidonic acids in vivo. J Biol Chem 274:16335–16341

    Google Scholar 

  33. Augusto O, Bonini MG, Amanso AM et al (2002) Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology. Free Radic Biol Med 32:841–859

    Article  PubMed  CAS  Google Scholar 

  34. Ford E, Hughes MN, Wardman P (2002) Kinetics of the reactions of nitrogen dioxide with glutathione, cysteine and uric acid at physiological pH. Free Radic Biol Med 32:1314–1323

    Article  PubMed  CAS  Google Scholar 

  35. Herold S, Rock G (2005) Mechanistic studies of S-nitrosothiol formation by NO•/O2 and by NO•/methemoglobin. Arch Biochem Biophys 436:386–396

    Article  PubMed  CAS  Google Scholar 

  36. Keszler A, Zhang Y, Hogg N (2010) Reaction between nitric oxide, glutathione, and oxygen in the presence and absence of protein: how are S-nitrosothiols formed? Free Radic Biol Med 48:55–64

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Beckman JS, Beckman TW, Chen J et al (1990) Apparent hydroxyl radical production by peroxynitrite-implications for endothelial injury from nitric-oxide and superoxide. Proc Natl Acad Sci U S A 87:1620–1624

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol Cell Physiol 40:C1424–C1437

    Google Scholar 

  39. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Radi R, Peluffo G, Alvarez MN et al (2001) Unraveling peroxynitrite formation in biological systems. Free Radic Biol Med 30:463–488

    Article  PubMed  CAS  Google Scholar 

  41. Squadrito GL, Pryor WA (1998) Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 25:392–403

    Article  PubMed  CAS  Google Scholar 

  42. Girouard H, Park L, Anrather J et al (2007) Cerebrovascular nitrosative stress mediates neurovascular and endothelial dysfunction induced by angiotensin II. Arterioscler Thromb Vasc Biol 27:303–309

    Article  PubMed  CAS  Google Scholar 

  43. Ushio-Fukai M (2009) Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 11:1289–1299

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Gregg D, de Carvalho DD, Kovacic H (2004) Integrins and coagulation: a role for ROS/redox signaling? Antioxid Redox Signal 6:757–764

    Article  PubMed  CAS  Google Scholar 

  45. Monteiro HP, Arai RJ, Travassos LR (2008) Protein tyrosine phosphorylation and protein tyrosine nitration in redox signaling. Antioxid Redox Signal 10:843–889

    Article  PubMed  CAS  Google Scholar 

  46. Liu H, Colavitti R, Rovira II et al (2005) Redox-dependent transcriptional regulation. Circ Res 97:967–974

    Article  PubMed  CAS  Google Scholar 

  47. Babior BM (1978) Oxygen-dependent microbial killing by phagocytes. N Engl J Med 298:659–668, 721–725

    Article  PubMed  CAS  Google Scholar 

  48. Babior BM (2004) NADPH oxidase. Curr Opin Immunol 16:42–47

    Article  PubMed  CAS  Google Scholar 

  49. Groemping Y, Rittinger K (2004) Activation and assembly of the NADPH oxidase: a structural perspective. Biochem J 386:401–416

    Google Scholar 

  50. Moldovan L, Mythreye K, Goldschmidt-Clermont PJ et al (2006) Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1. Cardiovas Res 71:236–246

    Article  CAS  Google Scholar 

  51. Sundaresan M, Yu ZX, Ferrans VJ et al (1996) Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J 318:379–382

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Sulciner DJ, Irani K, Yu ZH et al (1996) Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol 16:7115–7121

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Park HS, Lee SH, Park D et al (2004) Sequential activation of phosphatidylinositol 3-kinase, beta Pix, Rac1 and Nox1 in growth factor-induced production of H2O2. Mol Cell Biol 24:4384–4394

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Cho HJ, Jeong HG, Lee JS et al (2002) Oncogenic H-Ras enhances DNA repair through the Ras/phosphatidylinositol 3-kinase/Rac1 pathway in NIH3T3 cells. Evidence for association with reactive oxygen species. J Biol Chem 277:19358–19366

    Article  PubMed  CAS  Google Scholar 

  55. Gorin Y, Ricono JM, Kim NH et al (2003) Nox4 mediates Angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Ren Physiol 285:F219–F229

    CAS  Google Scholar 

  56. Chai D, Wang B, Shen L et al (2008) RXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cells. Free Radic Biol Med 44:1334–1347

    Article  PubMed  CAS  Google Scholar 

  57. Brown DI, Griendling KK (2009) Nox proteins in signal transduction. Free Radic Biol Med 47:1239–1253

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Miller FJ Jr (2009) NADPH oxidase 4: walking the walk with Poldip2. Circ Res 105:209–210

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Pelletier S, Duhamel F, Coulombe P et al (2003) Rho family GTPases are required for activation of JAK/STAT signaling by G protein-coupled receptors. Mol Cell Biol 23:1316–1333

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Taddei ML, Parri M, Mello T et al (2007) Integrin-mediated cell adhesion and spreading engage different sources of reactive oxygen species. Antioxid Redox Signal 9:469–481

    Article  PubMed  CAS  Google Scholar 

  61. van Wetering S, van Buul JD, Quik S et al (2002) Reactive oxygen species mediate Rac-induced loss of cell–cell adhesion in primary human endothelial cells. J Cell Sci 115:1837–1846

    PubMed  Google Scholar 

  62. Abid MR, Kachra Z, Spokes KC et al (2000) NADPH oxidase activity is required for endothelial cell proliferation and migration. FEBS Lett 486:252–256

    Article  PubMed  CAS  Google Scholar 

  63. Abid MR, Tsai JC, Spokes KC et al (2001) Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. FASEB J 15:2548–2550

    PubMed  CAS  Google Scholar 

  64. Yeh LH, Park YJ, Hansalia RJ et al (1999) Shear-induced tyrosine phosphorylation in endothelial cells requires Rac1-dependent production of ROS. Am J Physiol 276:C838–C847

    PubMed  CAS  Google Scholar 

  65. Sohn HY, Keller M, Gloe T et al (2000) The small G-protein Rac mediates depolarization-induced superoxide formation in human endothelial cells. J Biol Chem 275:18745–18750

    Article  PubMed  CAS  Google Scholar 

  66. Monaghan-Benson E, Burridge K (2009) The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species. J Biol Chem 284:25602–25611

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Beckers CM, van Hinsbergh VW, van Nieuw Amerongen GP (2010) Driving Rho GTPase activity in endothelial cells regulates barrier integrity. Thromb Haemost 103:40–55

    Article  PubMed  CAS  Google Scholar 

  68. Peppelenbosch MP, Qiu RG, de Vries-Smits AM et al (1995) Rac mediates growth factor-induced arachidonic acid release. Cell 81:849–856

    Article  PubMed  CAS  Google Scholar 

  69. Woo CH, Lee ZW, Kim BC et al (2000) Involvement of cytosolic phospholipase A2, and the subsequent release of arachidonic acid, in signalling by rac for the generation of intracellular reactive oxygen species in rat-2 fibroblasts. Biochem J 348:525–530

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Wu R, Coniglio SJ, Chan A et al (2007) Up-regulation of Rac1 by epidermal growth factor mediates COX-2 expression in recurrent respiratory papillomas. Mol Med 13:143–150

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Nimnual AS, Taylor LJ, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5:236–241

    Article  PubMed  CAS  Google Scholar 

  72. Wildenberg GA, Dohn MR, Carnahan RH et al (2006) p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho. Cell 127:1027–1039

    Article  PubMed  CAS  Google Scholar 

  73. Yang JQ, Li S, Domann FE et al (1999) Superoxide generation in v-Ha-ras-transduced human keratinocyte HaCaT cells. Mol Carcinog 26:180–188

    Article  PubMed  CAS  Google Scholar 

  74. Yang JQ, Buettner GR, Domann FE et al (2002) v-Ha-ras mitogenic signalling through superoxide and derived reactive oxygen species. Mol Carcinog 33:206–218

    Article  PubMed  CAS  Google Scholar 

  75. Weyemi U, Lagente-Chevallier O, Boufraqech M et al (2012) ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic HRas-induced DNA damage and subsequent senescence. Oncogene 31:1117–1129

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Weyemi U, Dupuy C (2012) The emerging role of ROS-generating NADPH oxidase NOX4 in DNA-damage responses. Mut Res 751:77–81

    Article  CAS  Google Scholar 

  77. Kodama R, Kato W, Furuta S et al (2013) Ros-generating oxidases NOX1 and NOX4 contribute to oncogenic Ras-induced premature senescence. Genes Cells 18:32–41

    Article  PubMed  CAS  Google Scholar 

  78. Lee AC, Fenster BE, Ito H et al (1999) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 274:7936–7940

    Article  PubMed  CAS  Google Scholar 

  79. Lee SB, Bae IH, Bae YS et al (2006) Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death. J Biol Chem 281:36228–36235

    Article  PubMed  CAS  Google Scholar 

  80. Daiber A (2010) Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 1797:897–906

    Article  PubMed  CAS  Google Scholar 

  81. Dikalov S et al (2011) Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 51:1289–1301

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Cassano S, Agnese S, D’Amato V et al (2010) Reactive oxygen species, Ki-Ras, and mitochondrial superoxide dismutase cooperate in nerve growth factor-induced differentiation of PC12 cells. J Biol Chem 285:24141–24153

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Cai W, Rudolph JL, Harrison SMW et al (2011) An evolutionary conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance. Mol Biol Cell 22:3231–3241

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Cai W, Shi G-X, Andres D (2013) Rit, p38 MAPK and oxidative stress. Commun Integr Biol 1:e22297

    Article  CAS  Google Scholar 

  85. Baker T, Booden M, Buss J (2000) S-Nitrosocysteine increases palmitate turnover on Ha-Ras in NIH 3T3 cells. J Biol Chem 275:22037–22047

    Article  PubMed  CAS  Google Scholar 

  86. Dawson TM, Sasaki M, Gonzalez-Zulueta M et al (1998) Regulation of neuronal nitric oxide synthase and identification of novel nitric oxide signaling pathways. Prog Brain Res 118:3–11

    Article  PubMed  CAS  Google Scholar 

  87. Lander HM, Hajjar DP, Hempstead BL et al (1997) A molecular redox switch on p21ras. Structural basis for the nitric oxide-p21Ras interaction. J Biol Chem 272:4323–4326

    Article  PubMed  CAS  Google Scholar 

  88. Lander HM, Milbank AJ, Tauras JM et al (1996) Redox regulation of cell signaling. Nature 381:380–381

    Article  PubMed  CAS  Google Scholar 

  89. Lander HM, Ogiste JS, Pearce SF et al (1995) Nitric oxide-stimulated guanine nucleotide exchange on p21ras. J Biol Chem 270:7017–7020

    Article  PubMed  CAS  Google Scholar 

  90. Lander HM, Sehajpal PK, Novogrodsky A (1993) Nitric oxide signaling: a possible role for G proteins. J Immunol 151:7182–7187

    PubMed  CAS  Google Scholar 

  91. Saavedra AP, Tsygankova OM, Prendergast GV et al (2002) Role of cAMP, PKA and Rap1A in thyroid follicular cell survival. Oncogene 21:778–788

    Article  PubMed  CAS  Google Scholar 

  92. Mittar D, Sehajpal PK, Lander HM (2004) Nitric oxide activates Rap1 and Ral in a Ras-independent manner. Biochem Biophys Res Commun 322:203–209

    Article  PubMed  CAS  Google Scholar 

  93. Lander HM, Tauras JM, Ogiste JS et al (1997) Activation of the receptor for advanced glycation end products triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272:17810–17814

    Article  PubMed  CAS  Google Scholar 

  94. Heo J, Prutzman KC, Mocanu V et al (2005) Mechanism of free radical nitric oxide-mediated Ras guanine nucleotide dissociation. J Mol Biol 346:1423–1440

    Article  PubMed  CAS  Google Scholar 

  95. Heo J, Campbell SL (2005) Superoxide anion radical modulates the activity of Ras and Ras-related GTPases by a radical-based mechanism similar to that of nitric oxide. J Biol Chem 280:12438–12445

    Article  PubMed  CAS  Google Scholar 

  96. Mallis RJ, Buss JE, Thomas JA (2001) Oxidative modification of H-Ras: S-thiolation and S-nitrosylation of reactive cysteines. Biochem J 355:145–153

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Heo J, Raines KW, Mocanu V et al (2006) Redox regulation of RhoA. Biochemistry 45:14481–14489

    Article  PubMed  CAS  Google Scholar 

  98. Aghajanian A, Wittchen ES, Campbell SL et al (2009) Direct activation of RhoA by reactive oxygen species requires a redox-sensitive motif. PLoS One 4:e8045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  100. Hu Y, Lu W, Chen G et al (2012) K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 22:399–412

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  101. Weinberg F, Hamanaka R, Wheaton WW et al (2010) Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107:8788–8793

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Kamp DW, Shacter E, Weitzman SA (2011) Chronic inflammation and cancer: the role of mitochondria. Oncology 25:400–410

    PubMed  Google Scholar 

  103. Bellot GL, Liu D, Pervaiz S (2012) ROS, autophagy, mitochondria and cancer: Ras, the hidden master? Mitochondrion 13:155–162

    Article  PubMed  CAS  Google Scholar 

  104. Kang J, Pervaiz S (2013) Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation? Front Oncol 2:206

    Article  PubMed  PubMed Central  Google Scholar 

  105. Nippert MM, O’Toole PS, Thorburn A (2006) Autophagy in cancer: good, bad, or both? Cancer Res 66:9349–9351

    Article  CAS  Google Scholar 

  106. Lock R, Roy S, Kenific CM et al (2011) Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 22:165–178

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  107. Guo JY, Chen H-Y, Fan J et al (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–470

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  108. Kim M-J, Woo S-J, Yoon C-H et al (2011) Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem 286:12924–12932

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Buyru N, Tigli H, Ozcan F et al (2003) Ras oncogene mutations in urine sediments of patients with bladder cancer. J Biochem Mol Biol 36:399–402

    Article  PubMed  CAS  Google Scholar 

  110. Choudhary S, Wang HCR (2007) Proapoptotic ability of oncogenic H-Ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells. Mol Cancer Ther 6:1099–1111

    Article  PubMed  CAS  Google Scholar 

  111. Choudhary S, Wang HCR (2009) Role of reactive oxygen species in proapoptotic ability of oncogenic H-Ras to increase human bladder cancer cell susceptibility to histone deacetylase inhibitor for caspase induction. J Cancer Res Clin Oncol 135:1601–1613

    Article  PubMed  CAS  Google Scholar 

  112. Choudhary S, Rathore K, Wang HCR (2011) Differential induction of reactive oxygen species through Erk1/2 and Nox-1 by FK288 for selective apoptosis of oncogenic H-Ras-expressing human urinary bladder cancer J82 cells. J Cancer Res Clin Oncol 137:471–480

    Article  PubMed  CAS  Google Scholar 

  113. Choudhary S, Rathore K, Wang HC (2010) FK228 and oncogenic H-Ras synergistically induce Mek1/2 and Nox1 to generate reactive oxygen species for differential cell death. Anticancer Drugs 21:831–840

    Article  PubMed  CAS  Google Scholar 

  114. Choudhary S, Wang KKA, Wang HCR (2011) Oncogenic H-Ras, FK228, and exogenous H2O2 cooperatively activated the ERK pathway in selective induction of human urinary bladder cancer J82 cell death. Mol Carcinogen 50:215–219

    Article  CAS  Google Scholar 

  115. Choudhary S, Sood S, Donnel RL et al (2012) Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Carcinogenesis 33:876–885

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  116. Deora AA, Hajjar DP, Lander HM (2000) Recruitment and activation of Raf-1 kinase by nitric oxide-activated Ras. Biochemistry 39:9901–9908

    Article  PubMed  CAS  Google Scholar 

  117. Ahmad R, Sylvester J, Ahmad M et al (2011) Involvement of H-Ras and reactive oxygen species in proinflammatory cytokine-induced matrix metalloproteinase-13 expression in human articular chondrocytes. Arch Biochem Biophys 507:350–355

    Article  PubMed  CAS  Google Scholar 

  118. Gabrielli A, Svegliati S, Moroncini G et al (2012) New insights into the role of oxidative stress in scleroderma fibrosis. Open Rheumatol J 6:87–95

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  119. Hordijk OL (2006) Regulation of NADPH oxidases: the role of Rac proteins. Circ Res 98:453–462

    Article  PubMed  CAS  Google Scholar 

  120. Harrison D, Griendling KK, Landmesser U et al (2003) Role of oxidative stress in atherosclerosis. Am J Cardiol 91:7A–11A

    Article  PubMed  CAS  Google Scholar 

  121. Lassegue B, Clempus RE (2003) Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 285:R277–R297

    PubMed  CAS  Google Scholar 

  122. Madamanchi NR, Vendrv A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25:29–38

    Article  PubMed  CAS  Google Scholar 

  123. Gregg D, Rauscher FM, Goldschmidt-Clermont PJ (2003) Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch. Am J Physiol Cell Physiol 285:C723–C734

    Article  PubMed  CAS  Google Scholar 

  124. Seshiah PN, Weber DS, Rocic P et al (2002) Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res 91:406–413

    Article  PubMed  CAS  Google Scholar 

  125. Zuo L, Ushio-Fukai M, Ikeda S et al (2005) Caveolin-I is essential for activation of Rac1 and NAD(P)H oxidase after angiotensin II type I receptor stimulation in vascular smooth muscle cells. Role in redox signaling and vascular hypertrophy. Arterioscler Thromb Vasc Biol 25:1824–1830

    Article  PubMed  CAS  Google Scholar 

  126. del Pozo MA, Balasubramanian N, Alderson NB et al (2005) Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat Cell Biol 7:901–908

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Vecchione C, Patrucco E, Marino G et al (2005) Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med 201:1217–1228

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  128. Kim K-S, Takeda K, Sethi R et al (1998) Protection from reoxygenation injury by inhibition of Rac1. J Clin Invest 101:1821–1826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  129. Harada N, Iimuro Y, Nitta T et al (2003) Inactivation of the small GTPase Rac1 protects the liver from ischemia/reperfusion injury in the rat. Surgery 134:480–491

    Article  PubMed  Google Scholar 

  130. Andreadis AA, Hazen SL, Comhair SA et al (2003) Oxidative and nitrosative events in asthma. Free Radic Biol Med 35:213–225

    Article  PubMed  CAS  Google Scholar 

  131. Rabe KF, Dent G, Magnussen H (1995) Hydrogen peroxide contracts human airways in vitro: role of epithelium. Am J Physiol 269:332–338

    Google Scholar 

  132. Kojima K, Kume H, Ito S et al (2007) Direct effects of hydrogen peroxide on airway smooth muscle tone: roles of Ca2+ influx and Rho-kinase. Eur J Pharmacol 556:151–156

    Article  PubMed  CAS  Google Scholar 

  133. Jin L, Ying Z, Webb RC (2004) Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 287:1495–1500

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy

    Elisa Ferro, Eva Baldini & Lorenza Trabalzini

  2. Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

    Luca Goitre & Saverio Francesco Retta

Authors
  1. Elisa Ferro
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  2. Luca Goitre
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  3. Eva Baldini
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  4. Saverio Francesco Retta
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  5. Lorenza Trabalzini
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Editor information

Editors and Affiliations

  1. University of Siena, Italy

    Lorenza Trabalzini

  2. University of Torino, Italy

    Saverio Francesco Retta

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Ferro, E., Goitre, L., Baldini, E., Retta, S.F., Trabalzini, L. (2014). Ras GTPases Are Both Regulators and Effectors of Redox Agents. In: Trabalzini, L., Retta, S. (eds) Ras Signaling. Methods in Molecular Biology, vol 1120. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-791-4_5

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  • DOI: https://doi.org/10.1007/978-1-62703-791-4_5

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-790-7

  • Online ISBN: 978-1-62703-791-4

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