Multidisciplinary Aspects of Regulatory Systems Relevant to Multiple Stressors: Aging, Xenobiotics and Radiation

Conference paper
Part of the NATO Science for Peace and Security Series book series (NAPSC)

Free-radical biology, which is central to the fields of radiation, aging and xenobiotics, has shifted from a paradigm highlighting damage to a paradigm emphasizing the role of free radicals in regulatory processes. A unified approach is possible since multiple stressors tend to activate a coordinated set of common mechanisms. These include antioxidant defenses, metal chelators, DNA repair systems, heat-shock proteins, xenobiotic efflux transporters, protein degradation systems, cell survival and apoptosis pathways and detoxification systems. Nearly all MAPK signal transduction pathways employ oxidative signaling, largely generated via membrane-bound NADPH oxidase systems. These regulate most cellular stress, growth and apoptotic responses. A new global perspective highlighting “Electroplasmic Cycles” incorporates numerous cellular aspects of control including free radicals, protein and histone modifications, nuclear–cytoplasmic transport, and ion channels. Aspects critical to multiple stressors include complex interactions related to apoptosis-necrosis, immunological responses (Toll-like receptors), bystander effects, chaperone proteins, and multiple xenobiotic efflux proteins. The synthesis suggests that a systems approach to multiple stressor impacts is required since understanding requires holistic appreciation of integrated regulatory circuitry.


Nuclear Export Nuclear Import Multiple Stressor Bystander Effect Nuclear Export Signal 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahn, K.S., Sethi, G., Jain, A.K., Jaiswal, A.K., and Aggarwal, B.B. 2006. Genetic deletion of NAD(P) H:quinone oxidoreductase 1 abrogates activation of nuclear factor-.B, IBBB kinase, C-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis. J. Biol. Chem. 281: 19798–808.Google Scholar
  2. Anders, H.J. 2005. A Toll for lupus. Lupus 14: 417–422.Google Scholar
  3. Arispe, N., Doh, M., Simakova, O., Kurganov, B., and De Maio, A. 2004. Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in decrease of viability. FASEB J. 18: 1636–645.Google Scholar
  4. Arnold-Schild, D., Hanau, D., Spehner, D., Schmid, C., Rammensee, H.G., de la Salle, H., and Schild, H. 1999. Cutting edge: Receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J. Immunol. 162: 3757–760.Google Scholar
  5. Arroyo, A., Modrianský, M., Serinkan, F.B., Bello, R.I., Matsura, T., Jiang, J., Tyurin, V.A., Tyurina, Y.Y., Fadeel, B., and Kagan, V.E. 2002. NADPH oxidase-dependent oxidation and externalization of phosphatidylserine during apoptosis in Me2SO-differentiated HL-60 cells: role in phagocytic clearance. J. Biol. Chem. 277: 49965–975.Google Scholar
  6. Asano, K., Miwa, M., Miwa, K., Hanayama, R., Nagase, H., Nagata, S., and Tanaka, M. 2004. Masking of phosphatidylserine inhibits cell engulfment and induces autoantibody production in mice. J. Exp. Med. 200: 459–467.Google Scholar
  7. Asea, A., Rehli, M., Kabingu, E., Boch, J.A., Bare, O., Auron, P.E., Stevenson, M.A., and Calderwood, S.K. 2002. Novel signal transduction pathway utilized by extracellular HSP70. J. Biol. Chem. 277: 15028–5034.Google Scholar
  8. Asehnoune, K., Strassheim, D., Mitra, S., Kim, J.Y., and Abraham, E. 2004. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-, B. J. Immunol. 172: 2522–529.Google Scholar
  9. Azzam, E.I., de Toledo, S.M., Spitz, D.R., and Little, J.B. 2002. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from v-particle-irradiated normal human fibroblast cultures. Cancer Res. 62: 5436–442.Google Scholar
  10. Bagatell, R. and Whitesell, L. 2004. Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol. Cancer Ther. 3: 1021–1030.Google Scholar
  11. Baker, E.K. and El-Osta, A. 2004. Epigenetics–normal control and deregulation in cancer: MDR1, chemotherapy and chromatin remodeling. Cancer Biol. Ther. 3: 819–824.Google Scholar
  12. Baker-LePain, J.C., Sarzotti, M., and Niccitta, C.V. 2004. Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4 + T cell Th1 cytokine production in vivo. J. Immunol. 172: 4195–203.Google Scholar
  13. Balaban, R.S., Nemoto, S., and Finkel, T. 2005. Mitochondria, oxidants and aging. Cell 120: 483–495.Google Scholar
  14. Baron, J.M., Goh, L.B., Yao, D., Wolf, R., and Friedberg, T. 2001. Modulation of P450 CYP3A4-dependent metabolism by P-glycoprotein: implications for P450 phenotyping. J. Pharmacol. Exp. Ther. 296: 351–358.Google Scholar
  15. Basu, S., Binder, R.J., Suto, R., Anderson, K.M., and Srivastava, P.K. 2000. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-BB pathway. Int. Immunol. 12: 1539–546.Google Scholar
  16. Bauer, G. 2002. Signaling and proapoptotic functions of transformed cell-derived reactive oxygen species. Prostagl. Leukot. Essen. Fatty Acids 66: 41–56.Google Scholar
  17. Beliakoff, J. and Whitesell, L. 2004. Hsp90: an emerging target for breast cancer therapy. Anti-Cancer Drugs 15: 651–662.Google Scholar
  18. Belli, F., Testori, A., Rivoltini, L., Maio, M., Andreola, G., Sertoli, M.R., Gallino, G., Piris, A., Cattelan, A., Lazzari, I., Carrabba, M., Scita, G., Santantonio, C., Pilla, L., Tragni, G., Lombardo, C., Arienti, F., Marchiano, A., Queirolo, P., Bertolini, F., Cova, A., Lamaj, E., Ascani, L., Camerini, R., Corsi, M., Cascinelli, N., Lewis, J.J., Srivastava, P., and Parmiani, G. 2002. Vaccination of metastatic melanoma patients with autologous tumor-derived heat-shock protein gp96-peptide complexes: clinical and immunologic findings. J. Clin. Oncol. 20: 4169–180.Google Scholar
  19. Berwin, B., Hart, J.P., Pizzo, S.V., and Nicchitta, C.V. 2002. CD91-independent cross-presentation of GRP94(gp96)-associated peptides. J. Immunol. 168: 4282–286.Google Scholar
  20. Binder, R.J. and Srivastava, P.K. 2004. Essential rosle of CD91 in re-presentation of gp96-chaperoned peptides. PNAS 101: 6128–133.Google Scholar
  21. Binder, R.J. and Srivastava, P.K. 2005. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nat. Immunol. 6: 593–599.Google Scholar
  22. Binder, R.J., Blachere, N.E., and Srivastava, P.K. 2001. Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatability complex I molecules. J. Biol. Chem. 276: 17163–171.Google Scholar
  23. Biswas, C., Sriram, U., Ciric, B., Ostrovsky, O., Gallucci, S., and Argon, Y. 2006. The N-terminal fragment of GRP94 is sufficient for peptide presentation via professional antigen-presenting cells. Intern. Immunol. 18:1147–157.Google Scholar
  24. Blachere, N.E., Li, Z., Chandawarkar, R.Y., Suto, R., Jaikaria, N.S., Basu, S., Udono, H., and Srivastava, P.K., 1997. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186: 1315–322.Google Scholar
  25. Blank, M. and Shoenfeld, Y. 2005. Experimental models of systemic lupus ertythematosus: anti-dsDNA in murine lupus. Rheumatology 44: 1086–1089.Google Scholar
  26. Brash, A.R. 2001. Arachidonic acid as a bioactive molecule. J. Clin. Invest. 107: 1339–345.Google Scholar
  27. Brash, D.E. and Havre, P.A. 2002. New careers for antioxidants. PNAS 99: 13969–971.Google Scholar
  28. Brownawell, A.M., Kops, G.J.P.L., Macara, I.G., and Burgering, B.M.T. 2001. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol. Cell. Biol. 21: 3534–546.Google Scholar
  29. Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S., Cheng, H.L., Jedrychowski, M.P., Gygi, S. P., Sinclair, D.A., Alt, F.W., and Greenberg, M.E. 2004. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015.Google Scholar
  30. Budd, S.L. and Lipton, S.A. 1998. Calcium tsunamis: do astrocytes transmit cell death messages via gap junctions during ischemia? Nat. Neurosci. 1: 431–432.Google Scholar
  31. Buzek, J., Latonen, L., Kuri, S., Peltonen, K., and Laiho, M. 2002. Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. Nucleic Acids Res. 30: 2340–348.Google Scholar
  32. Cai, H. 2005. NAD(P) H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease. Circ. Res. 96: 818–822.Google Scholar
  33. Callahan, M.K., Chaillot, D., Jacquin, C., Clark, P.R., and Menoret, A. 2002. Differential acquisition of antigenic peptides by Hsp70 and Hsc70 under oxidative conditions. J. Biol. Chem. 277: 33604–609.Google Scholar
  34. Carrero, P., Okamoto, K., Coumailleau, P., O’Brien, S., Tanaka, H., and Poellinger, L. 2000. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to Hypoxia-inducible factor 1p. Mol. Cell. Biol. 20: 402–415.Google Scholar
  35. Castellino, F., Boucher, P.E., Eichelberg, K., Mayhew, M., Rothman, J.E., Houghton, A.N., and Germain, R.N. 2000. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatability complex class I antigen presentation via two distinct processing pathways. J. Exp. Med. 191: 1957–964.Google Scholar
  36. Chang, M.K., Binder, C.J., Miller, Y.I., Subbanagounder, G., Silverman, G.J., Berliner, J.A., and Witztum, J.L. 2004. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J. Exp. Med. 200: 1359–370.Google Scholar
  37. Chen, J., Avdonin, V., Ciorba, M.A., Heinemann, S.H., and Hoshi, T. 2000. Acceleration of P/C-type inactivation of voltage-gated K+ channels by methionine oxidation. Biophys. J. 78: 174–187.Google Scholar
  38. Cherny, V.V., Henderson, L.M., Xu, W., Thomas, L.L., and DeCoursey, T.E. 2001. Activation of NADPH oxidase-related proton and electron currents in human eosinophils by arachidonic acid. J. Physiol. 535.3: 783–794.Google Scholar
  39. Chuang, T.H., Lee, J., Kline, L., Mathison, J.C., and Ulevitcjh, R.J. 2002. Toll-like receptor 9 mediates CpG-DNA signaling. J. Leukocyte Biol. 71: 538–544.Google Scholar
  40. Clejan, L.A. and Cederbaum, A.I. 1992. Role of cytochrome P450 in the oxidation of glycerol by reconstituted systems and microsomes. FASEB J. 6: 765–770.Google Scholar
  41. Coelho, D., Holl, V., Weltin, D., Lacornerie, T., Magnenet, P., Dufour, P., and Bischoff, P. 2000. Caspase-3-like activity determines the type of cell death following ionizing radiation in MOLT-4 human leukaemia cells. Br. J. Cancer 83: 642–649.Google Scholar
  42. Cooney, C.A., Dave, A.A., and Wolff, G.L. 2002. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J. Nutr. 132: 2393S–2400S.Google Scholar
  43. Courageot, M.P., Lépine, S., Hours, M., Giraud, F., and Sulpice, J.C. 2004. Involvement of sodium in early phosphatidylserine exposure and phospholipid scrambling induced by P2X7 purinoceptor activation in thymocytes. J. Biol. Chem. 279: 21815–823.Google Scholar
  44. Crane, J.K. and Vezina, C.M. 2005. Externalization of host cell protein kinase C during enteropathogenic Escherichia coli infection. Cell Death Different. 12: 115–127.Google Scholar
  45. Crawley, J.N. 1996. Unusual behavioral phenotypes of inbred mouse strains. Trends Neurosci. 19: 181–182.Google Scholar
  46. Cusato, K., Bosco, A., Rozental, R., Guimaraes, C.A., Reese, B.E., Linden, R., and Spray, D.C. 2003. Gap junctions mediate bystander cell death in developing brain. J. Neurosci. 23: 6413–422.Google Scholar
  47. DeCoursey, T.E. 2002. Voltage-gated proton channels and other proton transfer pathways. Physiol. Rev. 83: 475–579.Google Scholar
  48. Demine, R. and Walden, P. 2005. Testing the role of gp96 as peptide chaperone in antigen processing. J. Biol. Chem. 280: 17573–578.Google Scholar
  49. De Nardo, D., Masendycz, P., Ho, S., Cross, M., Fleetwood, A.J., Reynolds, E.C., Hamilton, J.A., Scholz, G.M. 2005. A central role for the Hsp90.Cdc37 molecular chaperone module in interleukin-1 receptor-associated-kinase-dependent signaling by Toll-like receptors. J. Biol. Chem. 280: 9813–822.Google Scholar
  50. Denny, M.F., Chandaroy, P., Killen, P.D., Caricchio, R., Lewis, E.E., Richardson, B.C., Lee, K.D., Gavalchin, J., and Kaplan, M.J. 2006. Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. J. Immunol. 176: 2095–2104.Google Scholar
  51. Dent, P., Yacoub, A., Contessa, J., Caron, R., Amorino, G., Valerie, K., Hagan, M.P., Grant, S., and Schmidt-Ullrich, R. 2003. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat. Res. 159: 283–300.Google Scholar
  52. Droge, W. 2002. Free radicals in the physiological control of cell function. Physiol. Rev. 82: 47–95.Google Scholar
  53. Droge, W. 2005. Oxidative aging and insulin receptor signaling. J. Gerontol. 60A: 1378–385.Google Scholar
  54. Esposito, F., Ammendola, R., Faraonio, R., Russo, T., and Cimino, F. 2004. Redox control of signal transduction, gene expression and cellular senescence. Neurochem. Res. 29: 617–628.Google Scholar
  55. Fadeel, B. 2003. Programmed cell clearance. Cell. Mol. Life Sci. 60: 2575–585.Google Scholar
  56. Fadeel, B. and Xue, D. 2006. PS externalization: from corpse clearance to drug delivery. Cell Death Different. 13: 360–362.Google Scholar
  57. Fahrenkrog, B. 2006. The nuclear pore complex, nuclear transport, and apoptosis. Can. J. Physiol. Pharmacol. 84: 279–286.Google Scholar
  58. Fan, J., Frey, R.S., and Malik, A.B. 2003. TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase. J. Clin. Invest. 112: 1234–243.Google Scholar
  59. Fathallah-Shaykh, H.M. 2005. Genomic discovery reveals a molecular system for resistance to oxidative and endoplasmic reticulum stress in cultured glioma. Arch. Neurol. 62: 233–236.Google Scholar
  60. Fedoroff, N. 2006. Redox regulatory mechanisms in cellular stress responses. Ann. Bot. 98: 289–300.Google Scholar
  61. Finkel, T. 2003. Oxidant signals and oxidative stress. Curr. Opin. Cell Biol. 15: 247–254.Google Scholar
  62. Finkel, M. and Cohen, H. 2005. Models of acetylation and the regulation of longevity: from yeast to humans. Drug Discov. Today Disease Models 2: 265–271.Google Scholar
  63. Fischer, J.L., Lancia, J.K., Mathur, A., Smith, M.L. 2006. Selenium protection from DNA damage involves a Ref1/p53/Brca1 protein complex. Anticancer Res. 26: 899–904.Google Scholar
  64. Fornace, A.J. Jr. 1992. Mammalian genes induced by radiation: activation of genes associated with growth control. Ann. Rev. Genet. 26: 507–526.Google Scholar
  65. Frankel, S. and Rogina, B. 2006. Sir2, caloric restriction and aging. Pathol. Biol. 54: 55–57.Google Scholar
  66. Frey, R.S., Gao, X., Javaid, K., Siddiqui, S.S., Rahman, A., and Malik, A.B. 2006. Phosphatidylinositol-3-kinase p signaling through protein kinase C induces NADPH oxidase-mediated oxidant generation and NF- B activation in endothelial cells. J. Biol. Chem. 281: 16128–138.Google Scholar
  67. Friedman, E.J. 2002. Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Curr. Pharm. Design 8: 1765–780.Google Scholar
  68. Furumoto, K., Inoue, E., Nagao, N., Hiyama, E., and Miwa, N. 1998. Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Life Sci. 63: 935–948.Google Scholar
  69. Geiszt, M. and Leto, T.L. 2004. The Nox family of NAD(P) H oxidases: host defense and beyond. J. Biol. Chem. 279: 51715–718.Google Scholar
  70. Gems, D. and McElwee, J.J. 2005. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech. Ageing Dev. 126: 381–387.Google Scholar
  71. Gidalevitz, T., Biswas, C., Ding, H., Schneidman-Duhovny, D., Wolfson, H.J., Stevens, F., Radford, S., and Argon, Y. 2004. Identification of the N-terminal peptide binding site of glucose-regulated protein 94. J. Biol. Chem. 279: 16543–552.Google Scholar
  72. Gilmour, P.S., Rahman, I., Donaldson, K., and MacNee, W. 2003. Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress from environmental particles. Am. J. Physiol. Lung Cell. Mol. Physiol. 284: L533–L540.Google Scholar
  73. Gingrich, J.A. and Hen, R. 2000. The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice. Curr. Opini. Neurobiol. 10: 146–152.Google Scholar
  74. Gong, B. and Almasan, A. 2000. Apo2 ligand/Tnf-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells. Cancer Res. 60: 5754–760.Google Scholar
  75. Haendeler, J., Hoffmann, J., Brandes, R.P., Zeiher, A.M., and Dimmeler, S. 2003. Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Mol. Cell. Biol. 23: 4598–610.Google Scholar
  76. Han, D., Canali, R., Rettori, D., and Kaplowitz, N. 2003. Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria, Mol. Pharmacol. 64: 1136–144.Google Scholar
  77. Harman, D. 1956. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11: 298–300.Google Scholar
  78. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., Akira, S. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408: 740–745.Google Scholar
  79. Herrlich, P., Bender, K., Knebel, A., Bohmer, F.D., Grob, S., Blattner, C., Rahmsdorf, H. J., and Gottlicher, M. 1999. Radiation-induced signal transduction: mechanisms and consequences. Compt. Rend. Acad. Sci. Ser. III, Sci.Vie 322: 121–125.Google Scholar
  80. Ho, G.T., Moodie, F.M., and Satsangi, J. 2003. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut 52: 759–766.Google Scholar
  81. Hopkins, P.A. and Sriskandan, S. 2005. Mammalian Toll-like receptors: to immunity and beyond. Clin. Exp. Immunol. 140: 395–407.Google Scholar
  82. Hoshino, H., Kobayashi, A., Yoshida, M., Kudo, N., Oyake, T., Motohashi, H., Hayashi, N., Yamamoto, M., and Igarashi, K. 2000. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J. Biol. Chem. 275: 15370–376.Google Scholar
  83. Huang, C.L., Huang, N.K., Shyue, S.K., and Chern, Y. 2003. Hydrogen peroxide induces loss of dopamine transporter activity: a calcium-dependent oxidative mechanism. J. Neurochem. 86: 1247–259.CrossRefGoogle Scholar
  84. Huber, J., Fürnkranz, A., Bochkov, V.N., Patricia M.K., Lee, H., Hedrick, C.C., Berliner, J.A., Binder, B.R., and Leitinger, N. 2006. Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase. J. Lipid Res. 47: 1054–1062.Google Scholar
  85. Ishii, K.J. and Akira, S. 2005. Innate immune recognition of nucleic acids: beyond toll-like receptors. Int. J. Cancer 117: 517–523.Google Scholar
  86. Itoh, M., Adachi, M., Yasui, H., Takekawa, M., Tanaka, H., and Imai, K. 2002. Nuclear export of glucocorticoid receptors is enhanced by c-Jun N-terminal kinase-mediated phosphorylation. Mol. Endocrinol. 16: 2382–392.Google Scholar
  87. Jackman, M., Kubota, Y., den Elzen, N., Hagting, A., and Pines, J. 2002. Cyclin A- and cyclin E-Cdk complexes shuttle between the nucleus and the cytoplasm. Mol. Biol. Cell 13: 1030–1045.Google Scholar
  88. Jackson, E.B., Theriot, C.A., Chattopadhyay, Mitra, S., and Izumi, T. 2005. Analysis of nuclear transport signals in the human apurunic/apyrimidinic endonuclease (APE1/Ref1). Nucleic Acids Res. 33: 3303–312.Google Scholar
  89. Jaenisch, R. and Bird, A. 2003. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. (Suppl.) 33: 245–254.Google Scholar
  90. Jans, D.A. 1995. The regulation of protein transport to the nucleus by phosphorylation. Biochem. J. 311: 705–716.Google Scholar
  91. Jazwinski, S.M. 1996. Longevity, genes and aging. Science 273: 54–59.Google Scholar
  92. Kagan, V.E., Borisenko, G.G., Serinkan, B.F., Tyurina, Y.Y., Tyurin, A., Jiang, J., Liu, S.X., Shvedova, A.A., Fabisiak, J.P., Uthaisang, W., and Fadeel, B. 2003. Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization, and recognition of phosphatidylserine. Am. J. Physiol. Lung Cell. Mol. Physiol. 285: L1–L17.Google Scholar
  93. Kang, H.L., Benzer, S., and Min, K.T. 2002. Life extension in Drosophila by feeding a drug. PNAS 99: 838–843.Google Scholar
  94. Kaplan, M.J., Lu, Q., Wu, A., Attwood, J., and Richardson, B. 2005. Demethylation of promoter regulatory elements contributes to performing overexpression in CD4+ lupus cells. J. Immunol. 172: 3652–661.Google Scholar
  95. Kawahara, T., Kuwano, Y., Teshima-Kondo, S., Takeya, R., Sumimoto, H., Kishi, K., Tsunawaki, S., Hirayama, T., and Rokutan, K. 2004. Role of nicotinamide adenine dinucleotide phosphate oxidase 1 in oxidative burst response to Toll-like receptor 5 signaling in large intestinal epithelial cells. J. Immunol. 172: 3051–3058.Google Scholar
  96. Kawahara, T., Kohjima, M., Kuwano, Y., Mino, H., Teshima-Kondo, S., Takeya, R., Tsunawaki, S., Wada, A., Sumimoto, H., and Rokutan, K. 2005. Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells. Am. J. Physiol. Cell Physiol. 288: 450–457.Google Scholar
  97. Kawai, T. and Akira, S. 2006. TLR signaling. Cell Death Different. 13: 816–825.Google Scholar
  98. Kleeberger, S.R., Reddy, S., Zhang, L.Y., and Jedlicka, A.E. 2000. Genetic susceptibility to ozone-induced lung hyperpermeability: Role of Toll-like receptor 4. Am. J. Resp. Cell Mol. Biol. 22: 620–627.Google Scholar
  99. Knoops, L., Haas, R.L., de Kemp, S., Broeks, A., van ‘t Veer, L.J., and de Jong, D. 2005. Low dose radiation induces a highly effective p53 response and rapid tumor regression in follicular lymphoma. Blood (ASH Annual Meeting Abstracts) 106: Abstract 354.Google Scholar
  100. Kodiha, M., Matusiewicz, N., and Stochaj, U. 2004. Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress. Cell Death Different. 11: 862–874.Google Scholar
  101. Kourie, J.I. 1998. Interaction of reactive oxygen species with ion transport mechanisms. Am. J. Physiol. Cell Physiol. 275: C1–C24.Google Scholar
  102. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.Y., and Campisi, J. 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. PNAS 98: 12072–2077.Google Scholar
  103. Kubota, H., Suzuki, T., Lu, J., Takahashi, S., Sugita, K., Sekiya, S., Suzuki, N. 2005. Increased expression of GRP94 protein is associated with decreased sensitivity to X-rays in cervical cancer cell lines. Int. J. Rad. Biol. 81: 701–709.Google Scholar
  104. Kudo, N., Taoka, H., Toda, T., Yoshida, M., and Horinouchi, S. 1999b. A novel nuclear export signal sensitive to oxidative stress in the fission yeast transcription factor Pap1. J. Biol. Chem. 274: 15151–158.Google Scholar
  105. Kudo, N., Matsumori, N., Taoka, H., Fujiwara, D., Schreiner, E.P., Wolff, B., Yoshida, M., and Horinouchi, S. 1999a. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. PNAS 96: 9112–117.Google Scholar
  106. Kuge, S., Arita, M., Murayama, A., Maeta, K., Izawa, S., Inoue, Y., d Nomoto, A. 2001. Regulation of the yeast Yap1p nuclear export signal is mediated by redox signal-induced reversible disulfide bond formation. Mol. Cell. Biol. 21: 6139–150.Google Scholar
  107. Kumaraguru, U., Pack, C.D., and Rouse, B.T. 2003. Toll-like receptor ligand links innate and adaptive immune responses by the production of heat-shock proteins. J. Leukocyte Biol. 73: 574–583.Google Scholar
  108. Kuo, S.S., Saad, A.H., Koong, A.C., Hahn, G.M., and Giaccia, A.J. 1993. Potassium-channel activation in response to low doses of u-Irradiation involves reactive oxygen intermediates in nonexcitatory cells. PNAS 90: 908–912.Google Scholar
  109. Kuroda, J., Nakagawa, K., Yamasaki, T., Nakamura, K., Takeya, R., Kuribayashi, F., Imajoh-Ohmi, S., Igarashi, K., Shibata, Y., Sueishi, K., and Sumimoto, H. 2005. The superoxide-producing NAD(P) H oxidase Nox4 in the nucleus of human vascular endothelial cells. Gennes Cells 10: 1139–151.Google Scholar
  110. Lancaster, G.L. and Febbraio, M.A. 2005. Exosome-dependent trafficking of HSP70. J. Biol. Chem. 280: 23349–355.Google Scholar
  111. Laroux, F.S., Romero, X., Wetzler, L., Engel, P., and Terhorst, C. 2005. Cutting Edge: MyD88 controls phagocyte NADPH oxidase function and killing of gram-negative bacteria. J. Immunol. 175: 5596–600.Google Scholar
  112. Leggas, M., Adachi, M., Scheffer, G.L., Sun, S., Wielinga, P., Du, G., Mercer, K.E., Zhuang, Y., Panetta, J.C., Johnston, B., Scheper, R.J., Stewart, C.F., and Schuetz, J.D. 2004. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell. Biol. 24: 7612–621.Google Scholar
  113. Leier, I., Jedlitschky, G., Buchholz, U., Center M., Cole, S.P.C., Deeley, R.G., and Keppler, D. 1996. ATP-dependent glutathione disulfide transport mediated by the MRP gene-encoded conjugate export pump. Biochem. J. 314: 433–437.Google Scholar
  114. Lemon, J.A., Boreham, D.R., and Rollo, C.D. 2003. A dietary supplement abolishes age-related cognitive decline in transgenic mice expressing elevated free radical processes, Exp. Biol. Med. 228: 800–810.Google Scholar
  115. Lescot, M., Rombauts, S., Zhang, J., Aubourg, S., Mathé, C., Jansson, S., Rouzé, P., and Boerjan, W. 2004. Annotation of a 95-kb Populus deltoides genomic sequence reveals a disease resistance gene cluster and novel class I and class II transposable elements. TGA Theor. Appl. Genet. 109: 10–22.Google Scholar
  116. Liu, B., Dai, J., and Li, Z. 2005a. Molecular and cellular mechanisms involved in the pathogenesis of autoimmune diseases induced by cell surface Gp96. Immunology 114: 144.Google Scholar
  117. Liu, B., Dai, J., Zheng, H., Stoilova, D., Sun, S., and Li, Z. 2003. Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. PNAS 100: 15824–15829.Google Scholar
  118. Liu, S., Wang, H., Yang, Z., Kon, T., Zhu, J., Cao, Y., Li, F., Kirkpatrick, J., Nicchitta, C.V., and Li, C.L. 2005b. Enhancement of cancer radiation therapy by use of adenovirus-mediated secretable glucose-regulated protein 94/gp96 expression. Cancer Res. 65: 9126–131.Google Scholar
  119. Macara, I.G. 2001. Transport into and out of the nucleus. Microbiol. Mol. Biol. Rev. 65: 570–590.Google Scholar
  120. Martin, G.M., Austad, S.N., and Johnson, T.E. 1996. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genetics 13: 25–34.Google Scholar
  121. McBride, W.H., Chaing, C.S., Olson, J.L., Wang, C.C., Hong, J.H., Pajonk, F., Dougherty, G.J., Iwamoto, K.S., Pervan, M., and Liao, Y.P. 2004. A sense of danger from radiation. Radiat. Res. 162: 1–19.Google Scholar
  122. McPhail, L.C., Qualliotine-Mann, D., Agwu, D.E., and McCall, C.E. 1993. Phospholipases and activation of the NADPH oxidase. Eur. J. Haematol. 51: 294–300.CrossRefGoogle Scholar
  123. Means, T.K., Latz, E., Hayashi, F., Murali, M.R., Golebock, D.T., and Luster, A.D. 2005. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115: 407–417.Google Scholar
  124. Meng, T.C., Lou, Y.W., Chen, Y.Y., Hsu, S.F., and Huang, Y.F. 2006. Cys-oxidation of protein tyrosine phosphatases: its role in regulation of signal transduction and its involvement in human cancers. J. Cancer Mol. 2: 9–16.Google Scholar
  125. Meplan, C., Richar, M.J., and Hainaut, P. 2000. Redox signalling and transition metals in the control of the p53 pathway. Biochem. Pharmacol. 59: 25–33.Google Scholar
  126. Merezak, C., Reichert, M., Van Lint, C., Kerkhofs, P., Portetelle, D., Willems, L., and Kettmann, R. 2002. Inhibition of histone deacytelases induces bovine leukemia virus expression in vitro and in vivo. J. Virol. 76: 5034–5042.Google Scholar
  127. Mevorach, D., Zhou, J.L., Song, X., and Elkon, K.B. 1998. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med. 188: 387–392.Google Scholar
  128. Milan, M., Campuzano, S., and Garcia-Bellido, A. 1997. Developmental parameters of cell death in the wing disc of Drosophila. PNAS 94: 5691–696.Google Scholar
  129. Miller, D.S., Graeff, C., Droulle, L., Fricker, S., and Fricker, G. 2002. Xenobiotic efflux pumps in isolated fish brain capillaries. Am. J. Physiol. Reg. Integ. Comp. Physiol. 282: 191–198.Google Scholar
  130. Minier, C., Eufemia, N., and Epel, D. 1999. The multi-xenobiotic resistance phenotype as a tool to biomonitor the environment. Biomarkers 4: 442–454.Google Scholar
  131. Mohan, C., Adams, S., Stanik, V., Datta, S.K. 1993. Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J. Exp. Med. 177: 1367–1381.Google Scholar
  132. Morgan, H.D., Sutherland, H.G.E., Martin, D.I.K., and Whitelaw, E. 1999. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23: 314–318.Google Scholar
  133. Narayanan, P.K., Goodwin, E.H., and Lehnert, B.E. 1997. Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Cancer Res. 57: 3963–971.Google Scholar
  134. Nimchuk, Z., Eulgem, T., Holt III, B.F., and Dangl, J.L. 2003. Recognition and response in the plant immune system. Ann. Rev. Genet. 37: 579–609.Google Scholar
  135. Norbury, C.C., Basta, S., Donohue, K.B., Tscharke, D.C., Princiotta, M.F., Berglund, P., Gibbs, J., Bennink, J.R., and Yewdell, J.W. 2004. CD8+ T cell cross-priming via transfer of proteasome substrates. Science 304: 1318–321.Google Scholar
  136. Obsil, T., Ghirlando, R., Anderson, D.E., Hickman, A.B., and Dyda, F. 2003. Two 14–3-3 binding motifs are required for stable association of forkhead transcription factor FOXO4 with 14–3-3 proteins and inhibition of DNA binding. Biochemistry 42: 15264–272.Google Scholar
  137. Okamoto, K., Tanaka, H., Ogawa, H., Makino, Y., Eguchi, H., Hayashi, S., Yoshikawa, N., Poellinger, L., Umesono, K., and Makino, I. 1999. Redox-dependent regulation of nuclear import of the glucocorticoid receptor. J. Biol. Chem. 274: 10363–371.Google Scholar
  138. Pardo, L.A., Contreras-Jurado, C., Zientkowska, M., Alves, F., Stuhmer, W. 2005. Role of voltage-gated potassium channels in cancer. J. Membr. Biol. 205: 115–124.Google Scholar
  139. Park, H.S., Jung, H.Y., Park, E.Y., Kim, J., Lee, W.J., and Bae, Y.S. 2004a. Cutting edge: Direct interaction of TLR4 with NAD(P) H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-tB. J. Immunol. 173: 3589–593.Google Scholar
  140. Park, J.Y., Ryang, Y.S., Shim, K.Y., Lee, J.I., and Kim, S.K. 2004b. NF-PB activation and regulation of toll-like receptors expression in human colon cancer cell line stimulated by DNA bis-intercalation agent, echinomycin. Proc. Amer. Assoc. Cancer Res. 45: Abstract #2259.Google Scholar
  141. Pennell, C.A., 2005. Heat shock proteins in immune response in the fall of 2004. Immunology 114: 297–300.Google Scholar
  142. Petosa, C., Schoehn, G., Askjaer, P., Bauer, U., Moulin, M., Steuerwald, U., Soler-Lopez, M., Baudin, F., Mattaj, I.W., and Muller, C.W. 2004. Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex. Mol. Cell 16: 761–775.Google Scholar
  143. Pletjushkina, O.Y., Fetisova, E.K., Lyamzaev, K.G., Ivanova, O.Y., Domnina, L.V., Vyssokikh, M.Y., Pustovidko, A.V., Vasiliev, J.M., Murphy, M.P., Chernyak, B.V., and Skulachev, V.P. 2005. Long-distance apoptotic killing of cells is mediated by hydrogen peroxide in a mitochondrial ROS-dependent fashion. Cell Death Different. 12: 1442–444.Google Scholar
  144. Pletjushkina, O.Y., Fetisova, E.K., Lyamzaev, K.G., Ivanova, O. Y., Domnina, L.V., Vyssokikh, M.Y., Pustovidko, A.V., Alexeevski, A.V., Alexeevski, D.A., Vasiliev, J.M., Murphy, M.P., Chernyak, B.V., and Skulachev, V.P. 2006. Hydrogen peroxide inside mitochondria takes part in cell-to-cell transmission of apoptotic signal. Biochemistry (Moscow) 71: 60–67.Google Scholar
  145. Poon, I.K.H. and Jans, D.A. 2005. Regulation of nuclear transport: central role in development and transformation? Traffic 6: 173–186.Google Scholar
  146. Powell, S.N. and Abraham, E.H. 1993. The biology of radioresistance: similarities, differences and interactions with drug resistance. Cytotechnology 12: 325–345.Google Scholar
  147. Prinz, M., Garbe, F., Schmidt, H., Mildner, A., Gutcher, I., Wolter, K., Piesche, M., Schroers, R., Weiss, E., Kirschning, C.J., Rochford, C.D.P., Bruck, W., and Becher, B. 2006. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116: 456–464.Google Scholar
  148. Proskuryakov, S.Y., Gabai, V.L., and Konoplyannikov, A.G. 2002. Necrosis is an active and controlled form of programmed cell death. Biochem. (Moscow) 67: 387–408.Google Scholar
  149. Qiao, B., Wu, J., Chu, Y.W., Wang, Y., Wang, D.P. Wu, H.S., and Xiong, S.D. 2005. Induction of systemic lupus erythematosus-like syndrome in syngeneic mice by immunization with activated lymphocyte-derived DNA. Rheumatology 44: 1108–114.Google Scholar
  150. Queitsch, C., Sangster, T.A., and Lindquist, S. 2002. Hsp90 as a capacitor of phenotypic variation. Nature 417: 618–624.Google Scholar
  151. Quintana, F.J. and Cohen, I.R. 2005. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J. Immunol. 175: 2777–782.Google Scholar
  152. Qureshi, S.T., Zhang, X., Bousette, N., Giaid, A., Shan, P., Medshitov, R.M., and Lee, P.J. 2006. Inducible activation of TLR4 confers resistance to hyperoxia-induced pulmonary apoptosis. J. Immunol. 176: 4950–958.Google Scholar
  153. Radic, M., Marion, T., and Monestier, M. 2004. Nucleosomes are exposed at the cell surface in apoptosis. J. Immunol. 172: 6692–700.Google Scholar
  154. Radsak, M.P., Hilf, N., Singh-Jasuja, H., Braedel, S., Brossart, P., Rammensee, H.G., and Schild, H. 2003. The heat shock protein gp96 binds to human neutrophils and monocytes and stimulates effector functions. Blood 101: 2810–815.Google Scholar
  155. Rapp, U.K. and Kaufmann, S.H.E. 2004. DNA vaccination with gp96-peptide fusion proteins induces protection against an intracellular bacterial pathogen. Int. Immunol. 16: 597–605.Google Scholar
  156. Renes, J., de Vries, E.G.E., Jansen, P.L.M., and Muller, M. 2000. The (patho) physiological functions of the MRP family. Drug Resistance Updates 3: 289–302.Google Scholar
  157. Reznikov, K., Kolesnikova, L., Pramanik, A., Tan-No, K., Gileva, I., Yakovleva, T., Rigler, R., Terenius, L., and Bakalkin, G. 2000. Clustering of apoptotic cells via bystander killing by peroxides. FASEB J. 14: 1754–764.Google Scholar
  158. Richards, T. and Budinger, T.F. 1988. NMR imaging and spectroscopy of the mammalian central nervous system after heavy ion radiation. Radiat. Res. 113: 79–101.Google Scholar
  159. Richardson, J.R., Caudle, W.M., Wang, M., Dean, E.D., Pennell, K.D., and Miller, G.W. 2006. Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson’s disease. FASEB J. 20: E976–E985.Google Scholar
  160. Robert, J., Menoret, A., and Cohen, N. 1999. Cell surface expression of the endoplasmic reticular heat shock protein gp96 is phylogenetically conserved. J. Immunol. 163: 4133–139.Google Scholar
  161. Rollo, C.D. 2002. Growth negatively impacts the life span of mammals. Evol. Develop. 4: 55–61.Google Scholar
  162. Rollo, C.D. 2006. Radiation and the regulatory landscape of neo2-Darwinism. Mutat. Res. 597: 18–31.Google Scholar
  163. Rollo, C.D. 2007. Overview of research on giant transgenic mice with emphasis on the brain and aging. In: T. Samaras (Ed.). Human body size and the laws of scaling. Nova Science Publishers, N.Y., pp. 235–260.Google Scholar
  164. Rollo, C.D., Carlson, J., and Sawada, M. 1996. Accelerated aging of giant transgenic growth hormone mice is associated with elevated free radical processes. Can. J. Zool. 74: 606–620.Google Scholar
  165. Ruppersberg, J.P., Stocker, M., Pongs, O., Heinemann, S.H., Frank, R., and Koenen, M. 1991. Regulation of fast inactivation of cloned mammalian Ik(A) channels by cysteine oxidation. Nature 352: 711–714.Google Scholar
  166. Rutherford, S.L. 2003. Between genotype and phenotype: protein chaperones and evolvability. Nat. Rev. Genet. 4: 263–274.Google Scholar
  167. Rutherford, S.L. and Lindquist, S. 1998. Hsp90 as a capacitor of phenotypic variation. Nature 396: 336–342.Google Scholar
  168. Sakakida, Y., Miyamoto, Y., Nagoshi, E., Akashi, M., Nakamura, T.J., Mamine, T., Kasahara, T., Minami, Y., Yoneda, Y., and Takumi, T. 2005. Importin n// mediates nuclear transport of a mammalian circadian clock component, mCRY2, together with mPER2, through a bipartite nuclear localization signal. J. Biol. Chem. 280: 13272–278.Google Scholar
  169. Sangster, T.A., Qeitsch, C., and Lindquist, S. 2003. Hsp90 and chromatin: where is the link? Cell Cycle 2: 166–168.Google Scholar
  170. Scarlett, D.J.G., Herst, P.M., and Berridge, M.V. 2005. Multiple proteins with single activities or a single protein with multiple activities: The conundrum of cell-surface NADH oxidoreductases. Biochim. Biophys. Acta 1708: 108–119.Google Scholar
  171. Schmidt-Ullrich, R.K., Dent, P., Grant, S., Mikkelsen, R.B., and Valerie, K. 2000. Signal transduction and cellular radiation responses. Radiat. Res. 153: 245–257.Google Scholar
  172. Schuetz, E.G., Umbenhauer, D.R., Yasuda, K., Brimer, C., Nguyen, L., Relling, M.V., Schuetz, J.D., and Schinkel, A.H. 2000. Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes. Mol. Pharmacol. 57: 188–197.Google Scholar
  173. Schulze-Lefert, P. 2004. Plant immunity: the origami of receptor activation. Curr. Biol. 14: R22–R24.Google Scholar
  174. Seo, Y.R., Kelly, M.R., and Smith, M.L. 2002. Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. PNAS 99: 14548–553.Google Scholar
  175. Shi, Y., Evans, J.E., and Rock, K.L. 2003. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425: 516–521.Google Scholar
  176. Shin, B.K., Wang, H., Yim, A.M., Le Naour, F., Brichory, F., Jang, J.H., Zhao, R., Puravs, E., Tra, J., Michael, C.W., Misek, D.E., and Hanash, S.M. 2003. Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J. Biol. Chem. 278: 7607–616.Google Scholar
  177. Sollars, V., Lu, X., Xiao, L., Wang, X., Garfinkel, M.D., and Ruden, D.M. 2003. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat. Genet. 33: 70–74.Google Scholar
  178. Sommer, T. and Jarosch, E. 2005. Pardon me–no access without ubiquitin. Dev. Cell 8: 4–5.Google Scholar
  179. Sorokin, A. 2004. Cyclooxygenase-2: potential role in regulation of drug efflux and multidrug resistance phenotype. Curr. Pharm. Design 10: 647–657.Google Scholar
  180. Soti, C., Subbarao, A., and Csermely, P. 2003. Apoptosis, necrosis and cellular senescence: chaperone occupancy as a potential switch. Aging Cell 2: 39–45.Google Scholar
  181. Srivastava, P. 2005. Specific immunogenicity of heat shock protein-peptide complexes: new developments. Cancer Immun. 5(Suppl. 1): 11.Google Scholar
  182. Stebbing, J., Bower, M., Nelson, M., Kebba, A.F., Gotch Patterson, S., and Gazzard, B. 2005. The role of HSPs and CD91 in the pathogenesis of HIV infection. Immunology 114: 148.Google Scholar
  183. Stolpen, A.H., Golan, D.E., and Pober, J.S. 1988. Tumor necrosis factor and immune interferon act in concert to slow lateral diffusion of proteins and lipids in human endothelial cell membranes. J. Cell Biol. 107: 781–789.Google Scholar
  184. Stommel, J.M., Marchenko, N.D., Jimenez, G.S., Moll, U.M., Hope, T.J., and Wahl, G.M. 1999. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18: 1660–672.Google Scholar
  185. Strom, A.C. and Weis, K. 2001. Importin-S-like nuclear transport receptors. Genome Biol. 2: 3008.1–30008.9.Google Scholar
  186. Stuart, J.A. and Brown, M.F. 2006. Energy, quiescence and the cellular basis of animal life spans. Comput. Biochem. Physiol. 143(Part A): 12–23.Google Scholar
  187. Takeshita, F., Leifer, C.A. Gursel, I., Ishii, K.J., Takeshita, S., Gurse, M., and Klinman, D.M. 2001. Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J. Immunol. 167: 3555–558.Google Scholar
  188. Tan, B., Piwnica-Worms, D., and Ratner, L. 2000. Multidrug resistance transporters and modulation. Cancer in AIDS. Curr. Opin. Oncol. 12:450–458.Google Scholar
  189. Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsutuo, T. 1992. Functional involvement of P-glycoprotein in blood-brain barrier. J. Biol. Chem. 267: 20383–20391.Google Scholar
  190. Toone, W.M., Kuge, S., Samuels, M., Morgan, B.A., Toda, T., and Jones, N. 1998. Regulation of the fission yeast transcription factor Pap1 by oxidative stress: requirement for nuclear export factor Crm1 (Exportin) and the stress-activated MAP kinase Sty1/Spc1. Genes Dev. 12: 1453–463.Google Scholar
  191. Tsan, M.F. and Gao, B. 2004a. Endogenous ligands of Toll-like receptors. J. Leukocyte Biol. 76: 514–519.Google Scholar
  192. Tsan, M.F. and Gao, E. 2004b. Cytokine function of heat shock proteins. Am. J. Physiol. Cell Physiol. 286: C739–C744.Google Scholar
  193. Tsunoda, I., Libbey, J.E., Kuang, L.Q., Terry, E.J., and Fujinami, R.S. 2005. Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis. Amer. J. Pathol. 167: 1631–646.Google Scholar
  194. Tyurina, Y.Y., Serinkan, F.B., Tyurin, V.A., Kini, V., Yalowich, J.C., Schroit, A.J., Fadeel, B., and Kagan, V.E. 2004. Lipid antioxidant, etoposide, inhibits phosphatidylserine externalization and macrophage clearance of apoptotic cells by preventing phosphatidylserine oxidation. J. Biol. Chem. 279: 6056–6064.Google Scholar
  195. Tyurina, Y.Y., Kini, V., Tyurin, V.A., Vlasova, I.I., Jiang, J., Kapralov, A.A., Belikova, N.A., Yalowich, J.C., Kurnikov, I.V., and Kagan, V.E. 2006. Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and antiapoptotic functions of etoposide. Mol. Pharmacol. 70: 706–717.Google Scholar
  196. Udono, H. and Srivastava, P.K. 1994. Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J. Immunol. 152: 5398–403.Google Scholar
  197. Uhr, M., Steckler, T., Yassouridis, A., and Holsboer, F. 2000. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to Mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 22: 380–387.Google Scholar
  198. Underhill, D.M. 2003. Toll-like receptors: networking for success. Eur. J. Immunol. 33: 1767–775.Google Scholar
  199. Velichkova, M. and Hasson, T. 2005. Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol. Cell. Biol. 25: 4501–513.Google Scholar
  200. Verdel, A., Curtet, S., Brocard, M.P., Rousseaux, S., Lemercier, C., Yoshida, M., and Khochbin, S. 2000. Active maintenance of mHDA2/mHDAC6 histone deacetylase in the cytoplasm. Curr. Biol. 10: 747–749.Google Scholar
  201. Vinken, M., Vanhaecke, T., Papeleu, P., Snykers, S., Henkens, T., and Rogiers, V. 2006. Connexins and their channels in cell growth and cell death. Cell. Signal. 18: 592–600.Google Scholar
  202. Voehringer, D.W., McConkey, D.J., McDonnell, T.J., Brisbay, S., and Meyn, R.E. 1998. Bcl-2 expression causes redistribution of glutathione to the nucleus. PNAS 95: 2956–960.Google Scholar
  203. von Gall, C., Garabette, M.L., Kell, C.A., Frenzel, S., Dehghani, F., Schumm-Draeger, P.M., Weaver, D.R., Kort, H.W., Hastings, M.H., and Stehle, J.H. 2002. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nat. Neurosci. 5: 234–238.Google Scholar
  204. Walther-Larsen, H., Brandt, J., Collinge, D.B., and Thordal-Christensen, H. 1993. A pathogen-induced gene of barley encodes a HSP90 homologue showing striking similarity to vertebrate forms resident in the endoplasmic reticulum. Plant Mol. Biol. 21: 1097–1108.Google Scholar
  205. Wang, H.D., Kazemi-Esfarjani, P., and Benzer, S. 2004. Multiple-stress analysis for isolation of Drosophila genes. PNAS 101: 12610–615.Google Scholar
  206. Wang, W., Yang, X., Kawai, T., de Silanes, I.L., Mazan-Mamczarz, K., Chen, P., Chook, Y.M., Quensel, C., Kohler, M., and Gorospe, M. 2004. AMP-activated protein kinase-regulated phosphorylation and acetylation of Importin t1. J. Biol. Chem. 279:48376–388.Google Scholar
  207. Wang, Y. and Tissenbaum, H.A. 2006. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Develop. 127: 48–56.Google Scholar
  208. Warger, T., Hilf, N., Rechtsteiner, G., Haselmayer, P., Carrick, D.M., Jonuleit, H., von Landenberg, P., Rammensee, H.G., Nicchitta, C.V., Radsak, M.P., and Schild, H. 2006. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. J. Biol. Chem. 281: 22545–553.Google Scholar
  209. Wiedlocha, A., Nilsen, T., Wesche, J., Sorensen, V., Malecki, J., Marcinkowska, E., and Olsnes, S. 2005. Phosphorylation-regulated nucleocytoplasmic trafficking of internalized fibroblast growth factor-1. Mol. Biol. Cell 16: 794–810.Google Scholar
  210. Wood, J.G., Rogina, B., Lavu, S., Howitz, K., Helfand, S.L., Tatar, M., and Sinclair, D. 2004. Sirtuin activators mimic caloric restriction and delay aging in metazoans. Nature 430: 686–689.Google Scholar
  211. Xue, L.Y., Butler, N.J., Makrigiorgos, G.M., Adelstein, S.J., and Kassis, A.I. 2002. Bystander effect produced by radiolabeled tumor cells in vivo. PNAS 99: 13765–770.Google Scholar
  212. Yabe, T., Suzuki, N., Furukawa, T., Ishihara, T., and Katsura, I. 2005. Multidrug resistance-associated protein MRP-1 regulates dauer diapause by its export activity in Caenorhabditis elegans. Development 132: 3197–207.Google Scholar
  213. Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., and Akira, S. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301: 640–643.Google Scholar
  214. Yi, A.K., Yoon, H., Park, J.E., Kim, B.S., Kim, H.J., and Martinez-Hernandez, A. 2006. CpG DNA-mediated induction of acute liver injury in D-galactosamine-sensitized mice: The mitochondrial apoptotic pathway-dependent death of hepatocytes. J. Biol. Chem. 281: 15001–5012.Google Scholar
  215. Zaman, G.J.R., Lankelma, J., Van Tellingen, O., Beijnen, J., Dekker, H., Paulusma, C., Oude Elferink, R.P.J., Baas, F., and Borst, P. 1995. Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. PNAS 92: 7690–694.Google Scholar
  216. Zhang, Q., Piston, D.W., and Goodman, R.H. 2002. Regulation of corepressor function by nuclear NADH. Science 295: 1895–897.Google Scholar
  217. Zhang, X., Shan, P., Qureshi, S., Homer, R., Medzhitov, R., Noble, P.W., and Lee, P.J. 2005. Cutting edge: TLR4 deficiency confers susceptibility to lethal oxidant lung injury. J. Immunol. 175: 4834–838.Google Scholar
  218. Zhang, Y. and Xiong, Y. 2001a. A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292: 1910–915.Google Scholar
  219. Zhang, Y. and Xiong, Y. 2001b. Control of p53 ubiquitination and nuclear export by MDM2 and ARF. Cell Growth Different. 12: 175–186.Google Scholar
  220. Zhao, X., Gan, L., Pan, H., Kan, D., Majeski, M., Adam, S.A., and Unterman, T.G. 2004. Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14–3-3-dependent and–independent mechanisms. Biochem. J. 378: 839–849.Google Scholar
  221. Zheng, L.M., Zychlinsky, A., Liu, C.C., Ojcius, D.M., and Young, J.D.E. 1991. Extracellular ATP as a trigger for apoptosis or programmed cell death. J. Cell Biol. 112: 279–288.Google Scholar
  222. Ziel, K.A., Grishko, V., Campbell, C.C., Breit, J.F., Wilson, G.L., and Gillespie, M.N. 2005. Oxidants in signal transduction: impact on DNA integrity and gene expression. FASEB J. 19: 387–394.Google Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  1. 1.Department of BiologyMcMaster UniversityCanada

Personalised recommendations