Molecular mechanisms of nitrogen dioxide induced epithelial injury in the lung

  • Rebecca L. Persinger
  • Matthew E. Poynter
  • Karina Ckless
  • Yvonne M. W. Janssen-Heininger
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 37)


The lung can be exposed to a variety of reactive nitrogen intermediates through the inhalation of environmental oxidants and those produced during inflammation. Reactive nitrogen species (RNS) include, nitrogen dioxide (•NO2) and peroxynitrite (ONOO-). Classically known as a major component of both indoor and outdoor air pollution, •NO2is a toxic free radical gas. •NO2can also be formed during inflammation by the decomposition of ONOO-or through peroxidase-catalyzed reactions. Due to their reactive nature, RNS may play an important role in disease pathology. Depending on the dose and the duration of administration, •NO2has been documented to cause pulmonary injury in both animal and human studies. Injury to the lung epithelial cells following exposure to •NO2is characterized by airway denudation followed by compensatory proliferation. The persistent injury and repair process may contribute to airway remodeling, including the development of fibrosis. To better understand the signaling pathways involved in epithelial cell death by •NO2, or other RNS, we routinely expose cells in culture to continuous gas-phase •NO2. Studies using the.•NO2, exposure system revealed that lung epithelial cell death occurs in a density dependent manner. In wound healing experiments, •NO2, induced cell death is limited to cells localized in the leading edge of the wound. Importantly, •NO2-induced death does not appear to be dependent on oxidative stress per se. Potential cell signaling mechanisms will be discussed, which include the mitogen activated protein kinase, c-Jun N-terminal Kinase and the Fas/Fas ligand pathways. During periods of epithelial loss and regeneration that occur in diseases such as asthma or during lung development, epithelial cells in the lung may be uniquely susceptible to death. Understanding the molecular mechanisms of epithelial cell death associated with the exposure to NO, will be important in designing therapeutics aimed at protecting the lung from persistent injury and repair. (Mol Cell Biochem 234/235: 71–80, 2002)

Key words

•NO2lung injury •NO2signaling mechanisms outdoor/indoor air pollution 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mustafa MG: Health effects and toxicology of ozone and nitrogen dioxide. In: J.O. Nrigau, M.S. Simmons (eds). Environmental Oxidants, Vol 28. John Wiley, New York, 1994, pp 351–404Google Scholar
  2. 2.
    Moldeus P: Toxicity induced by nitrogen dioxide in experimental animals and isolated cell systems. Scand J Work Environ Health 19 (suppl 2): 28–36, 1993PubMedGoogle Scholar
  3. 3.
    Bascom R: Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society. Health ef-fects of outdoor air pollution, Part 2. Am J Respir Crit Care Med 153: 477–498, 1996Google Scholar
  4. 4.
    Rennard SI, Romberger DJ, Sisson JH, Von Essen SG, Rubinstein I, Robbins RA, Spurzem JR: Airway epithelial cells: Functional roles in airway disease. Am J Respir Crit Care Med 150: 527–30, 1994Google Scholar
  5. 5.
    Berthiaume Y, Lesur 0, Dagenais A: Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium. Thorax 54: 150–160, 1999PubMedCrossRefGoogle Scholar
  6. 6.
    Adamson IY, Young L, Bowden DH: Relationship of alveolar epithelial injury and repair to the induction of pulmonary fibrosis. Am J Pathol 130: 377–383, 1988PubMedGoogle Scholar
  7. 7.
    Kaminsky DA, Mitchell J, Carroll N, James A, Soultanakis R, Janssen Y: Nitrotyrosine formation in the airways and lung parenchyma of patients with asthma. J Allergy Clin Immunol 104: 747–754, 1999PubMedCrossRefGoogle Scholar
  8. 8.
    Ichinose M, Sugiura H, Yamagata S, Koarai A, Shirato K: Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am J Respir Crit Care Med 162: 701706, 2000Google Scholar
  9. 9.
    Gaston B, Drazen JM, Loscalzo J, Stamler JS: The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149: 538–551, 1994PubMedGoogle Scholar
  10. 10.
    Chauhan AJ, Krishna MT, Frew AJ, Holgate ST: Exposure to nitrogen dioxide (NO2) and respiratory disease risk. Rev Environ Health 13: 73–90, 1998PubMedGoogle Scholar
  11. 11.
    Krishna MT, Chauhan AJ, Frew AL Holgate ST: Toxicological mechanisms underlying oxidant pollutant-induced airway injury. Rev Environ Health 13: 59–71, 1998PubMedGoogle Scholar
  12. 12.
    Hedberg K, Hedberg CW, Iber C, White KE, Osterholm MT, Jones DB, Flink JR, MacDonald KL: An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. J Am Med Assoc 262: 3014–3017,1989CrossRefGoogle Scholar
  13. 13.
    Goldstein E, Peek NF, Parks NJ, Hines HH, Steffey EP, Tarkington B: Fate and distribution of inhaled nitrogen dioxide in rhesus monkeys. Am Rev Respir Dis 115: 403–412, 1977PubMedGoogle Scholar
  14. 14.
    van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE: Reactive nitrogen species and tyrosine nitration in the respiratory tract: Epiphenomena or a pathobiologic mechanism of disease? Am J Respir Crit Care Med 160: 1–9, 1999PubMedGoogle Scholar
  15. 15.
    van der Vliet A, Eiserich JP, Marelich GP, Halliwell B, Cross CE: Oxidative stress in cystic fibrosis: Does it occur and does it matter? Adv Pharmacol 38: 491–513, 1997PubMedCrossRefGoogle Scholar
  16. 16.
    Wu W, Chen Y, Hazen SL: Eosinophil peroxidase nitrates protein tyrosyl residues. Implications for oxidative damage by nitrating intermediates in eosinophilic inflammatory disorders. J Biol Chem 274: 25933–25944,1999PubMedCrossRefGoogle Scholar
  17. 17.
    Byun J, Mueller DM, Fabjan JS, Heinecke JW: Nitrogen dioxide radical generated by the myeloperoxidase-hydrogen peroxide-nitrite system promotes lipid peroxidation of low density lipoprotein. FEBS Lett 455: 243–246, 1999PubMedCrossRefGoogle Scholar
  18. 18.
    Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Am J Physiol 271: C1424–1437, 1996PubMedGoogle Scholar
  19. 19.
    Salvemini D, Wang ZQ, Stern MK, Currie MG, Misko TP: Peroxynitrite decomposition catalysts: Therapeutics for peroxynitrite-mediated pathology. Proc Natl Acad Sci USA 95: 2659–2663, 1998PubMedCrossRefGoogle Scholar
  20. 20.
    Floris R, Piersma SR, Yang G, Jones P, Weyer R: Interaction of myeloperoxidase with peroxynitrite. A comparison with lactoperoxidase, horseradish peroxidase and catalase. Eur J Biochem 215: 767–775, 1993PubMedCrossRefGoogle Scholar
  21. 21.
    van der Vliet A, Eiserich JP, Halliwell B, Cross CE: Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional mechanism of nitric oxide-dependent toxicity. J Biol Chem 272: 7617–7625, 1997PubMedCrossRefGoogle Scholar
  22. 22.
    Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A: Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391: 393–397, 1998PubMedCrossRefGoogle Scholar
  23. 23.
    Pryor WA, Squadrito GL: The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. Am J Physiol 268: L699–722, 1995PubMedGoogle Scholar
  24. 24.
    Postlethwait EM, Bidani A: Reactive uptake governs the pulmonary air space removal of inhaled nitrogen dioxide. J Appl Physiol 68: 594–603, 1990PubMedGoogle Scholar
  25. 25.
    Miller FJ, Overton JH, Myers ET, Graham JA: Pulmonary dosimetry of nitrogen dioxide in animals and man. In: T. Schineider, L. Grant (eds). Air Pollution by Nitrogen Oxides. Elsevier, Amsterdam, 1988, pp 377–386Google Scholar
  26. 26.
    Holroyd KJ, Eleff SM, Zhang LY, Jakab GJ, Kleeberger SR: Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice. Am J Physiol 273: L595–602, 1997PubMedGoogle Scholar
  27. 27.
    Evans MJ, Johnson LV, Stephens RJ, Freeman G: Renewal of the terminal bronchiolar epithelium in the rat following exposure to NO2, or 03. Lab Invest 35: 246–257, 1976PubMedGoogle Scholar
  28. 28.
    Barth PJ, Muller B: Effects of nitrogen dioxide exposure on Clara cell proliferation and morphology. Pathol Res Pract 195: 487–493, 1999PubMedCrossRefGoogle Scholar
  29. 29.
    Rombout PJ, Dormans JA, Marra M, van Esch GJ: Influence of exposure regimen on nitrogen dioxide-induced morphological changes in the rat lung. Environ Res 41: 466–480, 1986PubMedCrossRefGoogle Scholar
  30. 30.
    Foster JR, Cottrell RC, Herod IA, Atkinson HA, Miller K: A comparative study of the pulmonary effects of NO2in the rat and hamster. Br J Exp Pathol 66: 193–204, 1985PubMedGoogle Scholar
  31. 31.
    Parkinson DR, Stephens RJ: Morphological surface changes in the terminal bronchiolar region of NO2-exposed rat lung. Environ Res 6: 37–51, 1973PubMedCrossRefGoogle Scholar
  32. 32.
    Azoulay-Dupuis E, Torres M, Soler P, Moreau J: Pulmonary NO2, toxicity in neonate and adult guinea pigs and rats. Environ Res 30: 322–339, 1983PubMedCrossRefGoogle Scholar
  33. 33.
    Kleinerman J: Some effects of nitrogen dioxide on the lung. Fed Proc 36: 1714–1718, 1977PubMedGoogle Scholar
  34. 34.
    Sadeghi-Hashjin G, Folkerts G, Henricks PA, Verheyen AK, van der Linde HJ, van Ark I, Coene A, Nijkamp FP: Peroxynitrite induces airway hyperresponsiveness in guinea pigsin vitroandin vivo.Am J Respir Crit Care Med 153: 1697–1701, 1996PubMedGoogle Scholar
  35. 35.
    Samet JM, Pepelko WE, Sonawane B, Hatch GE, Driscoll KE, Oberdorster G: Risk assessment of oxidant gases and particulate air pollutants: Uncertainties and research needs. Environ Health Perspect 102 (suppl 10): 209–213, 1994PubMedCrossRefGoogle Scholar
  36. 36.
    Persinger RL, Blay WM, Heintz NH, Hemenway DR, Janssen-Heininger YMW: Nitrogen dioxide induces death in lung epithelial cells in a density-dependent manner. Am J Respir Cell Mol Biol 24: 1–8, 2001Google Scholar
  37. 37.
    Walles SA, Victorin K, Lundborg M: DNA damage in lung cellsin vivoandin vitroby 1,3-butadiene and nitrogen dioxide and their photochemical reaction products. Mutat Res 328: 11–19, 1995PubMedCrossRefGoogle Scholar
  38. 38.
    Bermudez E, Ferng SF, Castro CE, Mustafa MG: DNA strand breaks caused by exposure to ozone and nitrogen dioxide. Environ Res 81: 72–80, 1999PubMedCrossRefGoogle Scholar
  39. 39.
    Schneiderman MH, Schneiderman GS: Targets for radiation-induced cell death: When dna damage doesn’t kill. Radiat Res 155: 529–535, 2001PubMedCrossRefGoogle Scholar
  40. 40.
    Mead JF, Gan-Elephano M, Hirahara F: Initiation of peroxidation by nitrogen dioxide in natural and modern membrane systems. In: S.D. Lee (ed.). Nitrogen Oxides and Their Effects on Health. Ann Arbor Science Publishers, Ann Arbor, MI, 1980, pp 191–197Google Scholar
  41. 41.
    Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B, Barnes S, Kirk M, Freeman BA: Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem 269: 26066–26075, 1994PubMedGoogle Scholar
  42. 42.
    Radi R, Beckman JS, Bush KM, Freeman BA: Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288: 481–487, 1991PubMedCrossRefGoogle Scholar
  43. 43.
    Darley-Usmar VM, Hogg N, O’Leary VJ, Wilson MT, Moncada S: The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radie Res Commun 17: 9–20, 1992CrossRefGoogle Scholar
  44. 44.
    Sagai M, Ichinose T, Kubota K: Studies on the biochemical effects of nitrogen dioxide. IV. Relation between the change of lipid peroxidation and the antioxidative protective system in rat lungs upon life span exposure to low levels of NO,. Toxicol Appl Pharmacol 73: 444–456, 1984PubMedCrossRefGoogle Scholar
  45. 45.
    Kelly FJ, Tetley TD: Nitrogen dioxide depletes uric acid and ascorbic acid but not glutathione from lung lining fluid. Biochem J 325: 95–99, 1997PubMedGoogle Scholar
  46. 46.
    Chow CK, Tappel AL: Response of glutathione peroxidase to dietary selenium in rats. J Nutr 104: 444–451, 1974PubMedGoogle Scholar
  47. 47.
    Aoshiba K, Yasui S, Nishimura K, Nagai A: Thiol depletion induces apoptosis in cultured lung fibroblasts. Am J Respir Cell Mol Biol 21: 54–64, 1999PubMedGoogle Scholar
  48. 48.
    Rahman Q, Abidi P, Afaq F, Schiffmann D, Mossman BT, Kamp DW, Athar M: Glutathione redox system in oxidative lung injury. Crit Rev Toxicol 29: 543–568, 1999PubMedCrossRefGoogle Scholar
  49. 49.
    Takahashi Y, Oakes SM, Williams MC, Takahashi S, Miura T, Joyce-Brady M: Nitrogen dioxide exposure activates gamma-glutamyl transferase gene expression in rat lung. Toxicol Appl Pharmacol 143: 388–396, 1997PubMedCrossRefGoogle Scholar
  50. 50.
    Lymar SV, Hurst JK: Carbon dioxide: Physiological catalyst for peroxynitrite-mediated cellular damage or cellular protectant? Chem Res Toxicol 9: 845–850, 1996PubMedCrossRefGoogle Scholar
  51. 51.
    Ohshima H, Friesen M, Brouet I, Bartsch H: Nitrotyrosine as a new marker for endogenous nitrosation and nitration of proteins. Food Chem Toxicol 28: 647–652, 1990PubMedCrossRefGoogle Scholar
  52. 52.
    van der Vliet A, Eiserich JP, O’Neill CA, Halliwell B, Cross CE: Tyrosine modification by reactive nitrogen species: A closer look. Arch Biochem Biophys 319: 341–349, 1995PubMedCrossRefGoogle Scholar
  53. 53.
    Heinecke JW: Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis. Curr Opin Lipidol 8: 268–274, 1997PubMedCrossRefGoogle Scholar
  54. 54.
    Haddad IY, Pataki G, Hu P, Galliani C, Beckman JS, Matalon S: Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J Clin Invest 94: 2407–2413, 1994PubMedCrossRefGoogle Scholar
  55. 55.
    Kooy NW, Royall JA, Ye YZ, Kelly DR, Beckman JS: Evidence forin vivoperoxynitrite production in human acute lung injury. Am J Respir Crit Care Med 151: 1250–1254, 1995PubMedGoogle Scholar
  56. 56.
    Saleh D, Barnes PJ, Giaid A: Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 155: 1763–1769, 1997PubMedGoogle Scholar
  57. 57.
    MacMillan-Crow LA, Crow JP, Thompson JA: Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 37: 1613–1622, 1998PubMedCrossRefGoogle Scholar
  58. 58.
    Haddad IY, Zhu S, Ischiropoulos H, Matalon S: Nitration of surfactant proteinAresults in decreased ability to aggregate lipids. Am J Physiol 270: L281–288, 1996PubMedGoogle Scholar
  59. 59.
    van der Vliet A, Hristova M, Cross CE, Eiserich JP, Goldkorn T: Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells. J Biol Chem 273: 31860–31866, 1998PubMedCrossRefGoogle Scholar
  60. 60.
    Eiserich JP, Estevez AG, Bamberg TV, Ye YZ, Chumley PH, Beckman JS, Freeman BA: Microtubule dysfunction by posttranslational nitrotyrosination of alpha-tubulin: A nitric oxide-dependent mecha-nism of cellular injury. Proc Natl Acad Sci USA 96: 6365–6370, 1999PubMedCrossRefGoogle Scholar
  61. 61.
    Cassina AM, Hodara R, Souza JM, Thomson L, Castro L, Ischiropoulos H, Freeman BA, Radi R: Cytochrome c nitration by peroxynitrite. J Biol Chem 275: 21409–21415, 2000PubMedCrossRefGoogle Scholar
  62. 62.
    Ip YT, Davis RJ: Signal transduction by the c-Jun N-terminal kinase (JNK) - from inflammation to development. Curr Opin Cell Biol 10: 205–219, 1998PubMedCrossRefGoogle Scholar
  63. 63.
    Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR: The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156–160, 1994PubMedCrossRefGoogle Scholar
  64. 64.
    Schaeffer HJ, Weber MJ: Mitogen-activated protein kinases: Specific messages from ubiquitous messengers. Mol Cell Biol 19: 2435–2444, 1999PubMedGoogle Scholar
  65. 65.
    Robinson MJ, Cobb MH: Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9: 180–186, 1997PubMedCrossRefGoogle Scholar
  66. 66.
    Smith A, Ramos-Morales F, Ashworth A, Collins M: A role for JNK/ SAPK in proliferation, but not apoptosis, of IL-3-dependent cells. Curr Biol 7: 893–896, 1997PubMedCrossRefGoogle Scholar
  67. 67.
    Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell 103: 239–252, 2000PubMedCrossRefGoogle Scholar
  68. 68.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326–1331,1995PubMedCrossRefGoogle Scholar
  69. 69.
    Janssen-Heininger YM, Macara I, Mossman BT: Cooperativity between oxidants and tumor necrosis factor in the activation of nuclear factor (NF)-kappaB: requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappaB by oxidants. Am J Respir Cell Mol Biol 20: 942–952, 1999PubMedGoogle Scholar
  70. 70.
    Go YM, Patel RP, Maland MC, Park H, Beckman JS, Darley-Usmar VM, Jo H: Evidence for peroxynitrite as a signaling molecule in flow-dependent activation of c-Jun NH(2)terminal kinase. Am J Physiol 277: H1647–1653, 1999PubMedGoogle Scholar
  71. 71.
    Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ: Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15: 2760–2770, 1996PubMedGoogle Scholar
  72. 72.
    Lawler S, Fleming Y, Goedert M, Cohen P: Synergistic activation of SAPKI /JNK I by two MAP kinase kinasesin vitro.Curr Biol 8: 13871390, 1998Google Scholar
  73. 73.
    Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ: The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Mol Cell Biol 19: 1569–1581, 1999PubMedGoogle Scholar
  74. 74.
    Smeal T, Binetruy B, Mercola DA, Birrer M, Karin M: Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354: 494–496, 1991PubMedCrossRefGoogle Scholar
  75. 75.
    Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR: Phosphorylation of c-jun mediated by MAP kinases. Nature 353: 670–674, 1991PubMedCrossRefGoogle Scholar
  76. 76.
    Whitmarsh AJ, Davis RJ: Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 74: 589–607, 1996PubMedCrossRefGoogle Scholar
  77. 77.
    Sluss HK, Barrett T, Derijard B, Davis RJ: Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol 14: 8376–8384, 1994PubMedGoogle Scholar
  78. 78.
    Kallunki T, Su B, Tsigelny I, Sluss HK, Derijard B, Moore G, Davis R, Karin M: JNK2 contains a specificity-determining region respon-sible for efficient c-Jun binding and phosphorylation. Genes Dev 8: 2996–3007, 1994PubMedCrossRefGoogle Scholar
  79. 79.
    Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ: Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870–874, 2000PubMedCrossRefGoogle Scholar
  80. 80.
    Constant SL, Dong C, Yang DD, Wysk M, Davis RJ, Flavell RA: JNK1 is required for T cell-mediated immunity against Leishmania major infection. J Immunol 165: 2671–2676, 2000PubMedGoogle Scholar
  81. 81.
    Yang DD, Conze D, Whitmarsh AJ, Barrett T, Davis RJ, Rincon M, Flavell RA: Differentiation of CD4+ T cells to Thl cells requires MAP kinase JNK2. Immunity 9: 575–585, 1998PubMedCrossRefGoogle Scholar
  82. 82.
    Dong C, Yang DD, Tournier C, Whitmarsh AJ, Xu J, Davis RJ, Flavell RA: JNK is required for effector T-cell function but not for T-cell activation. Nature 405: 91–94, 2000PubMedCrossRefGoogle Scholar
  83. 83.
    Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ: A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 277: 693–696, 1997PubMedCrossRefGoogle Scholar
  84. 84.
    Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA: Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389: 865–870, 1997PubMedCrossRefGoogle Scholar
  85. 85.
    Behrens A, Sibilia M, Wagner EF: Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21: 326–329, 1999PubMedCrossRefGoogle Scholar
  86. 86.
    Hreniuk D, Garay M, Gaarde W, Monia BP, McKay RA, Cioffi CL: Inhibition of C-Jun N-terminal kinase 1, but not c-Jun N-terminal kinase 2, suppresses apoptosis induced by ischemia/reoxygenation in rat cardiac myocytes. Mol Pharmacol 59: 867–874, 2001PubMedGoogle Scholar
  87. 87.
    Behrens A, Sabapathy K, Graef I, Cleary M, Crabtree GR, Wagner EF: Jun N-terminal kinase 2 modulates thymocyte apoptosis and T cell activation through c-Jun and nuclear factor of activated T cell (NF-AT). Proc Natl Acad Sci USA 98: 1769–1774, 2001PubMedCrossRefGoogle Scholar
  88. 88.
    Eichhorst ST, Muller M, Li-Weber M, Schulze-Bergkamen H, Angel P, Krammer PH: A novel AP-1 element in the CD95 ligand promoter is required for induction of apoptosis in hepatocellular carcinoma cells upon treatment with anticancer drugs. Mol Cell Biol 20: 7826–7837, 2000PubMedCrossRefGoogle Scholar
  89. 89.
    Faris M, Latinis KM, Kempiak SJ, Koretzky GA, Nel A: Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter. Mol Cell Biol 18: 5414–5424, 1998PubMedGoogle Scholar
  90. 90.
    Kasibhatla S, Brunner T, Genestier L, Echeverri F, Mahboubi A, Green DR: DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B andAP-I. Mol Cell 1: 543–551, 1998PubMedCrossRefGoogle Scholar
  91. 91.
    Kolbus A, Herr I, Schreiber M, Debatin KM, Wagner EF, Angel P: cJun-dependent CD95-L expression is a rate-limiting step in the induction of apoptosis by alkylating agents. Mol Cell Biol 20: 575–582, 2000PubMedCrossRefGoogle Scholar
  92. 92.
    Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW: Differential requirement for caspase 9 in apoptotic pathwaysin vivo.Cell 94: 339–352, 1998PubMedCrossRefGoogle Scholar
  93. 93.
    Woo M, Hakem R, Soengas MS, Duncan GS, ShahinianA, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW: Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 12: 806–819, 1998PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Rebecca L. Persinger
    • 1
  • Matthew E. Poynter
    • 2
  • Karina Ckless
    • 2
  • Yvonne M. W. Janssen-Heininger
    • 2
  1. 1.Department of Environmental Health, School of Public Health and Community MedicineUniversity of WashingtonSeattle
  2. 2.Department of PathologyUniversity of Vermont College of MedicineBurlingtonUSA

Personalised recommendations