The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein bag-1

Journal of Virology

Volumn 77, Issue 2, 2003, Pages 1292-1305

  Perkins, D ^a   Pereira, E F R ^a   Aurelian, L ^a,b  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MARYLAND   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BAG 1 PROTEIN; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN BAD; PROTEIN BCL 2; RIBONUCLEOTIDE REDUCTASE; STRESS ACTIVATED PROTEIN KINASE; UNCLASSIFIED DRUG;

ANIMAL CELL; APOPTOSIS; ARTICLE; BRAIN NERVE CELL; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; GENE DELETION; HERPES SIMPLEX VIRUS 1; HERPES SIMPLEX VIRUS 2; HIPPOCAMPUS; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN STABILITY; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION; VIRUS MUTANT;

ACTIVATING TRANSCRIPTION FACTOR 2; ANIMALS; APOPTOSIS; CARRIER PROTEINS; CASPASE 3; CASPASES; CERCOPITHECUS AETHIOPS; CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN; DNA-BINDING PROTEINS; ENZYME ACTIVATION; HERPESVIRUS 1, HUMAN; HERPESVIRUS 2, HUMAN; HIPPOCAMPUS; MITOGEN-ACTIVATED PROTEIN KINASES; NEURONS; POLY(ADP-RIBOSE) POLYMERASES; PROTEIN-SERINE-THREONINE KINASES; RIBONUCLEOTIDE REDUCTASES; TRANSCRIPTION FACTORS; UP-REGULATION; VERO CELLS;

EID: 0037228190     PISSN: 0022538X     EISSN: None     Source Type: Journal    
DOI: 10.1128/JVI.77.2.1292-1305.2003     Document Type: Article

References (92)

1. Alkondon, M., and E. X. Albuquerque. 1993. Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes. J. Pharmacol. Exp. Ther. 265:1455-1473.
2. Aubert, M., and J. A. Blaho. 1999. The herpes simplex virus type 1 regulatory protein IC27 is required for the prevention of apoptosis in infected human cells. J. Virol. 73:2803-2813.
3. Aurelian, L., and C. C. Smith. 2000. Herpes simplex type 2 growth and latency reactivation by cocultivation are inhibited with antisense oligonucleotides complementary to the translation initiation site of the large subunit of ribonucleotide reductase (RRI). Antisense Nucleic Acid Drug Dev. 10:77-85.
4. Aurelian, L., C. C. Smith, R. Winchurch, M. Kulka, L. Zaccaro, T. Gyotoku, F. J. Chrest, and J. W. Burnett. 2001. A novel gene expressed in human keratinocytes with long term growth potential is required for cell growth. J. Investig. Dermatol. 116:286-295.
5. Banker, G., and K. Goslin. 1998. Types of nerve cell cultures, their advantages and limitations, p. 11-39. In G. Banker and K. Goslin (ed.), Culturing Nerve Cells, 2nd Ed. MIT Press, Cambridge, Mass.
6. Behrens, A., M. Sibilis, and E. F. Wagner. 1999. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat. Genet. 21:326-329.
7. Bennett, B. L., D. T. Sasaki, B. W. Murray, E. C. O'Leary, S. T. Sakata, W. Xu, J. C. Leistein, A. Motiwala, S. Pierce, Y. Satoh, S. S. Bhagwat, A. M. Manning, and D. W. Anderson. 2001. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 98:13681-13686.
8. Bergstrom, T., B. Svennerholm, N. Conradi, P. Horal, and A. Vahlne. 1991. Discrimination of herpes simplex types 1 and 2 cerebral infections in a rat model. Acta Neuropathol. 82:395-401.
9. Birge, R. B., E. Fajardo, and Hempstead, B. L. 1998. Signal transduction and neuronal cell death during development and disease, p. 347-383. In R. A. Lockshin, Z. Zakeri, and J. L. Tilly (ed.), When Cells Die. Wiley Liss, New York, N.Y.
10. Bonni, A., A. Brunet, A. E. West, S. R. Datta, M. A. Takasu, and M. E. Greenberg. 1999. Cell survival promoted by the Ras-mitogen-activated protein kinase signaling pathway by transcription-dependent and independent mechanisms. Science 286:1358-1362.
11. Bossy-Wetzel, E., L. Bakiri, and M. Yaniv. 1997. Induction of apoptosis by the transcription factor c-Jun. EMBO J. 16:1695-1709.
12. Bossy-Wetzel, E., D. D. Newmeyer, and D. R. Green. 1998. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independent of mitochondrial transmembrane depolarization. EMBO J. 17:37-49.
13. Bothwell, M. 1991. Keeping track of neurotrophin receptors. Cell 65:915-918.
14. Cheung, N. S., P. M. Beart, C. J. Pascoe, C. A. John, and O. Bernard. 2000. Human Bcl-2 protects against AMPA receptor-mediated apoptosis. J. Neurochem. 74:1613-1620.
15. 134.5 gene of herpes simplex virus type 1 precludes neuroblastoma cells from triggering total shut off of protein synthesis characteristic of programmed cell death in neuronal cells. Proc. Natl. Acad. Sci. USA 89:3266-3270.
16. Chung, T. D., J. P. Wymer, C. C. Smith, M. Kulka, and L. Aurelian. 1989. Protein kinase activity associated with the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). J. Virol. 63:3389-3398.
17. Cookson, M. R., P. G. Ince, P. A. Usher, and P. J. Shaw. 1999. Poly(ADP-ribose) polymerase is found in both the nucleus and cytoplasm of human central nervous system neurons. Brain Res. 834:182-185.
18. Dent, P., D. B. Reardon, D. K. Morrison, and T. W. Sturgill. 1995. Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro. Mol. Cell. Biol. 15:4125-4135.
19. Eilers, A., J. Whitfield, B. Shah, C. Spadoni, H. Desmond, and J. Ham. 2001. Direct inhibition of c-Jun N-terminal kinase in sympathetic neurons prevents c-jun promoter activation and nerve growth factor withdrawal-induced death. J. Neurochem. 76:1439-1454.
20. English, J. D., and J. D. Sweatt. 1996. Activation of p42 mitogen-activated protein kinase in hippocampal long-term potentiation. J. Biol. Chem. 271:24329-24332.
21. Fadeel, B., B. Zhivotovsky, and S. Orrenius. 1999. All along the watchtower: On the regulation of apoptosis regulators. FASEB J. 13:1647-1657.
22. Favata, M. F., K. Y. Horluchi, E. J. Manos, A. J. Daulerl, D. A. Stradley, W. S. Feeser, D. E. Van Dyk, W. J. Pitts, R. A. Earl, F. Hobbs, R. A. Copeland, R. L. Magolda, P. A. Scherle, and J. M. Trzaskos. 1998. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273:18623-18632.
23. Ferreira, A., and A. Caceres. 1992. Expression of the class III beta-tubulin isotype in developing neurons in culture. J. Neurosci. Res. 32:516-529.
24. Finkbeiner, S., S. F. Tavazoie, A. Maloratsky, K. M. Jacobs, K. M. Harris, and M. E. Greenberg. 1997. CREB: A major mediator of neuronal neurotrophin responses. Neuron 19:1031-1047.
25. Francois, F., M. J. Godinho, and M. L. Grimes. 2000. CREB is cleaved by caspases during neural cell apoptosis. FEBS Lett. 486:281-284.
26. Fuchs, S. Y., V. Adler, M. R. Pincus, and Z. Ronai. 1998. MEKK1/JNK signaling stabilizes and activates p53. Proc. Natl. Acad. Sci. USA 95:10541-10546.
27. Garrido, C., S. Gurbuxani, L. Ravagnan, and G. Kroemer. 2001. Heat shock proteins: Endogenous modulators of apoptotic cell death. Biochem. Biophys. Res. Commun. 286:433-442.
28. Gavrieli, Y., Y. Sherman, and S. A. Ben-Sasson. 1992. Identification of programmed cell death via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119:493-501.
29. Glorioso, J. C., and D. J. Fink. 2002. Use of HSV vectors to modify the nervous system. Curr. Opin. Drug Discov. Dev. 5:289-295.
30. Gold, R., M. Schmied, G. Giegerich, H. Beitschopf, H. P. Hartung, K. V. Toyka, and H. Lassman. 1994. Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab. Investig. 71:219-225.
31. Goldstein, D. J., and S. K. Weller. 1987. Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: Isolation and characterization of an ICP6 lacZ insertion mutant. J. Virol. 62:196-205.
32. Goldstein, D. J., and S. K. Weller. 1988. Factor(s) present in herpes simplex virus type 1-infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: Characterization of an ICP6 deletion mutant. Virology 166:41-51.
33. Grandgirard, D., E. Studer, L. Monney, T. Belser, I. Fellay, C. Borner, and M. R. Michel. 1998. Alphaviruses induce apoptosis in Bcl-2-overexpressing cells: Evidence for a caspase-mediated, proteolytic inactivation of Bcl-2. EMBO J. 17:1268-1278.
34. Gupta, S., T. Barrett, A. J. Whitmarsh, J. Cavanagh, H. K. Sluss, B. Derijard, and R. Davis. 1996. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15:2760-2770.
35. Ham, J., C. Babij, J. Whitfield, C. M. Pfarr, D. Lallemand, M. Yaniv, and L. L. Rubin. 1995. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14:927-939.
36. Han, Z., D. L. Boyle, L. Chang, B. Bennett, M. Karin, L. Yang, A. M. Manning, and G. S. Firestein. 2001. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Investig. 108:73-81.
37. Hardwick, J. M., G. Ketner, and R. J. Clem. 1998. Viral genes that modulate apoptosis, p. 243-279. In J. W. Wilson, C. Booth, and C. S. Potten (ed.), Apoptosis Genes. Kluwer Academic Publishers, Dordrecht, The Netherlands.
38. Hata, S., A. H. Koyama, H. Shiota, A. Adachi, F. Goshima, and Y. Nishiyama. 1999. Anti-apoptotic activity of herpes simplex virus type 2: The role of US3 protein kinase gene. Microbes Infect. 1:601-607.
39. Hayashi, T., K. Sakai, C. Sasaki, Y. Itoyama, and K. Abe. 2000. Loss of bag-1 immunoreactivity in rat brain after transient middle cerebral artery occlusion. Brain Res. 852:496-500.
40. Herdegen, T., A. Blume, T. Buschmann, E. Georgakopoulos, C. Winter, W. Schmid, T. F. Hsieh, M. Zimmermann, and P. Gass. 1997. Expression of activating transcription factor-2, serum response factor and cAMP/Ca response element binding protein in the adult rat brain following generalized seizures, nerve fibre lesion and ultraviolet irradiation. Neuroscience 81:199-212.
41. Hoffmeyer, A., A. Grosse-Wilde, E. Flory, B. Neufeld, M. Kunz, U. R. Rapp, and S. Ludwig. 1999. Different mitogen-activating protein kinase signaling pathways cooperate to regulate tumor necrosis factor gene expression in T lymphocytes. J. Biol. Chem. 274:4319-4327.
42. Honig, L. S., and R. N. Rosenberg. 2000. Apoptosis and neurologic disease. Am. J. Med. 108:317-330.
43. Horie, M., Y. Mitsumoto, H. Kyushiki, N. Kanemoto, A. Watanabe, Y. Taniguchi, N. Nishino, T. Okamoto, M. Kondo, T. Mori, K. Noguchi, Y. Nakamura, E. Takahashi, and A. Tanigami. 2000. Identification and characterization of TMEFF2, a novel survival factor for hippocampal and mesencephalic neurons. Genomics 67:146-152.
44. Hyman, B. T., G. W. Van Hoesen, and A. R. Damasio. 1990. Memory-related neural systems in Alzheimer's disease: An anatomic study. Neurology 40:1721-1730.
45. Ishizuka, T., N. Terada, P. Gerwins, E. Hamelmann, A. Oshiba, G. R. Fanger, G. L. Johnson, and E. W. Gelfand. 1997. Mast cell tumor necrosis factor is regulated by MEK kinases. Proc. Natl. Acad. Sci. USA 94:6358-6363.
46. Ivins, K. J., J. K. Ivins, J. P. Sharp, and C. W. Cotman. 1999. Multiple pathways of apoptosis in PC12 cells. CrmA inhibits apoptosis induced by β-amyloid. J. Biol. Chem. 274:2107-2112.
47. Jerome, K. R., R. Fox, Z. Chen, A. E. Sears, H.-Y. Lee, and L. Corey. 1999. Herpes simplex virus inhibits apoptosis through the action of two genes, US5 and US3. J. Virol. 73:8950-8957.
48. Johnson Webb, S., D. J. Harrison, and A. H. Wyllie. 1997. Apoptosis: An overview of the process and its relevance in disease. Adv. Pharmacol. 41:1-31.
49. Kaplan, D. R., and F. D. Miller. 2000. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10:381-391.
50. Kitamura, Y., S. Shimohama, W. Kamoshima, T. Ota, Y. Matsuoka, Y. Nomura, M. A. Smith, G. Perry, P. J. Whitehouse, and T. Taniguchi. 1998. Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease. Brain Res. 780:260-269.
51. Kyriakis, J. M., and J. Avruch. 1996. Sounding the alarm: Protein kinase cascades activated by stress and inflammation. J. Biol. Chem. 271:24313-24316.
52. Lackey, K., M. Cory, R. Davis, S. V. Frye, P. A. Harris, R. N. Hunter, D. K. Jung, O. B. McDonald, R. W. McNutt, M. R. Peel, R. D. Rutkowske, J. M. Veal, and E. R. Wood. 2000. The discovery, of potent cRaf1 kinase inhibitors. Bioorg. Med. Chem. Lett. 10:223-226.
53. Levresse, V., L. Butterfield, E. Zentrich, and L. E. Heasley. 2000. Akt negatively regulates c-Jun N-terminal kinase pathway in PC12 cells. J. Neurosci. Res. 62:799-808.
54. Lewis, T. S., P. S. Shapiro, and N. G. Ahn. 1998. Signal transduction through mitogen-activated protein kinase cascade. Adv. Cancer. Res. 74:49-139.
55. Luo, J., and L. Aurelian. 1992. The transmembrane helical segment but not the invariant lysine is required for the kinase activity of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). J. Biol. Chem. 267:9645-9653.
56. Masquilier, D., and P. Sassone-Corsi. 1992. Transcriptional cross-talk: Nuclear factors CREM and CREB bind to alkaline phosphatase-1 sites and inhibit activation by Jun. J. Biol. Chem. 267:22460-22466.
57. McLean, T. I., and S. L. Bachenheimer. 1999. Activation of c-Jun terminal kinase by herpes simplex virus type 1 enhances viral replication. J. Virol. 73:8415-8426.
58. Milne, D. M., L. E. Campbell, D. G. Campbell, and D. W. Meek. 1995. p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase JNK1. J. Biol. Chem. 270:5511-5518.
59. Minden, A., and M. Karin. 1997. Regulation and function of the JNK subgroup of mitogen-activated protein kinases. Biochim. Biophys. Acta 1333: F85-F104.
60. Morishima, Y., Y. Gotoh, J. Zieg, T. Barrett, H. Takano, R. Flavell, R. J. Davis, Y. Shirasaki, and M. E. Greenberg. 2001. Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-jun N-terminal kinase pathway and the induction of Fas ligand. J. Neurosci. 21:7551-7560.
61. Munger, J., and B. Roizman. 2001. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc. Natl. Acad. Sci USA 98:10410
62. Newcomb, R., X. Sun, I. Taylor, N. Curthoys, and R. G. Fiffard. 1997. Increased production of extracellular glutamate by the mitochondrial glutaminase following neuronal death. J. Biol. Chem. 272:11276-11282.
63. Nicholson, D. W., A. Ali, N. A. Thornberry, J. P. Vaillancourt, C. K. Ding, M. Gallant, Y. Gareau, P. R. Griffin, M. Labelle, Y. A. Lazebnik, N. A. Munday, S. M. Raju, M. E. Smulson, T.-T. Yamin, V. L. Yu, and D. K. Miller. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37-43.
64. Noguchi, K., C. Kitanaka, H. Yamana, A. Kokubu, T. Mochizuki, and Y. Kuchino. 1999. Regulation of c-Myc trough phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J. Biol. Chem. 274:32580-32587.
65. Otterson, O. P. 1991. Excitatory amino acid neurotransmitters: Anatomical systems, p. 14-38. In B. S. Meldrum (ed.), Excitatory Amino Acid Antagonists. Blackwell Scientific, Oxford, UK.
66. Perkins, D., E. F. R. Pereira, M. Gober, P. J. Yarowsky, and L. Aurelian. 2002. The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) blocks apoptosis in hippocampal neurons involving activation of the MEK/mitogen-activated protein kinase survival pathway. J. Virol. 76:1435-1449.
67. Perkins, D., Y. X. Yu, L. L. Bambrick, P. J. Yarwosky, and L. Aurelian. 2002. Expression of herpes simplex virus type 2 protein ICP10 PK rescues neurons from apoptosis due to serum deprivation or genetic defects. Exp. Neurol. 174:118-122.
68. Perkins, D., K. A. Gyure, E. F. R. Pereira, and L. Aurelian. Herpes simplex virus type 1 induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. J. Neurovirol., in press.
69. Perng, G.-C., C. Jones, J. Ciacci-Zanella, M. Stone, G. Henderson, A. Yukht, S. M. Slanina, F. M. Hofman, H. Ghiasi, A. B. Nesburn, and S. L. Wechsler. 2000. Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 287:1500-1503.
70. Reed, J. C. 1994. Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124:1-6.
71. Riccio, A., S. Ahn, C. M. Davenport, J. A. Blendy, and D. D. Ginty. 1999. Mediation by a CREB family transcription factor of nerve growth factor-dependent survival of sympathetic neurons. Science 286:2358-2361.
72. Schulz, J. B., D. Bremen, J. C. Reed, J. Lommatzsch, S. Takayama, U. Wullner, P.-A. Loschmann, T. Klockgether, and M. Weller. 1997. Cooperative interception of neuronal apoptosis by Bcl-2 and Bag-1 expression: Prevention of caspase activation and reuced production of reactive oxygen species. J. Neurochem. 69:2075-2086.
73. Smith, C. C., J. H. Luo, J. C. R. Hunter, J. V. Ordonez, and L. Aurelian. 1994. The transmembrane domain of the large subunit of HSV-2 ribonucleotide reductase (ICP10) is required for protein kinase activity and transformation-related signaling pathways that result in ras activation. Virology 200:598-612.
74. Smith, C. C., and L. Aurelian. 1997. The large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) is associated with the virion tegument and has PK activity. Virology 234:235-242.
75. Smith, C. C., T. Peng, M. Kulka, and L. Aurelian. 1998. The protein kinase domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) is required for immediate-early gene expression and virus growth. J. Virol. 72:9131-9141.
76. Smith, C. C., J. Nelson, L. Aurelian, M. Gober, and B. B. Goswami. 2000. Ras-GAP binding/phosphorylation by herpes simplex virus type 2 RR1 protein kinase (ICP10) and activation of the Ras/MEK/mitogen-activated protein kinase mitogenic pathway are required for timely onset of virus growth. J. Virol. 74:10417-10429.
77. Smith, C. C., Y. X. Yu, M. Kulka, and L. Aurelian. 2000. A novel human gene similar to the PK coding domain of the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10) codes for a serine-threonine PK and is expressed in melanoma cells. J. Biol. Chem. 275:25690-25699.
78. Soh, J.-W., E. H. Lee, R. Prywes, and B. Weinstein. 1999. Novel roles of specific isoforms of protein kinase C in activation of the c-fos serum response element. Mol. Cell. Biol. 19:1313-1324.
79. Takayama, S., T. Sato, S. Krajewski, K. Kochel, S. Irie, J. A. Millan, and J. C. Reed. 1995. Cloning and functional analysis of BAG-1: A novel Bcl-2 binding protein with anti-cell death activity. Cell 80:279-284.
80. Tran, S. E. F., T. H. Holmstrom, M. Ahonen, V-M, Kahari, and J. E. Eriksson. 2001. Mitogen-activated protein kinase/ERK overrides the apoptotic signaling from Fas, tumor necrosis factor alpha, and TRAIL receptors. J. Biol. Chem. 276:16484-16490.
81. Van Dam, H., D. Wilhelm, I. Herr, A. Steffen, P. Herlich, and P. Angel. 1995. ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic stress. EMBO J. 14:1798-1811.
82. Wang, H.-G., S. Takayama, U. R. Rapp, and J. C. Reed. 1996. Bcl-2 interacting protein Bag-1 binds to and activates the kinase Raf-1. Proc. Natl. Acad. Sci. USA 93:7063-7068.
83. Wang, H.-G., U. R. Rapp, and J. C. Reed. 1996. Bcl-2 targets the protein kinase Raf-1 to the mitochondria. Cell 87:629-638.
84. Wang, H.-G., N. Pathan, I. M. Ethel, S. Krajewski, Y. Yamaguchi, F. Shibasaki, F. McKeon, T. Bobo, T. F. Franke, and J. C. Reed. 1999. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339-343.
85. Xu, L., R. M. Sapolsky, and R. G. Giffard. 2001. Differential sensitivity of murine astrocytes and neurons from different brain regions to injury. Exp. Neurol. 169:416-424.
86. Xu, Z., A. C. Maroney, P. Dobranski, N. V. Kukekov, and L. A. Greene. 2001. The MLK-mediated c-Jun N-terminal kinase activation in neuronal apoptosis. Mol. Cell. Biol. 21:4713-4724.
87. Yan, C. Y. I., and L. A. Greene. 1998. Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. J. Neurosci. 18:4042-4049.
88. Yang, E., J. Zha, J. Jockel, L. H. Boise, C. B. Thomson, and S. J. Korsmeyer. 1995. Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285-291.
89. Yuan, J., and B. A. Yankner. 2000. Apoptosis in the nervous system. Nature 407:802-809.
90. Zachos, G., B. Clements, and J. Conner. 1999. Herpes simplex virus type 1 infection stimulates p38/c-Jun N-terminal mitogen-activated protein kinase pathways and activates transcription factor alkaline phosphatase-1. J. Biol. Chem. 274:5097-5103.
91. Zachos, G., M. Koffa, C. M. Preston, J. B. Clements, and J. Conner. 2001. Herpes simplex virus type 1 blocks the apoptotic host cell defense mechanisms that target Bcl-2 and manipulates activation of p38 mitogen-activated protein kinase to improve viral replication. J. Virol. 75:2710-2728.
92. Zha, J., H. Harada, E. Yang, J. Jockel, and S. J. Korsmeyer. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3, not BCL-X(L). Cell 87:619-628.