Skip to main content
SpringerLink
Log in

Transcriptional Regulation of the BCL-X Gene by NF-κB Is an Element of Hypoxic Responses in the Rat Brain

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Signal transduction pathways that mediate neuronal commitment to apoptosis involve the nuclear factor kappa B (NF-κB) transcription factor. The bcl-x gene is a member of the bcl-2 family of genes that regulate apoptosis, and gives rise to two proteins, Bcl-XL and Bcl-XS, via alternative mRNA splicing. Bcl-XL protein, like Bcl-2, is a dominant inhibitor of apoptotic cell death, whereas Bcl-XS promotes apoptosis. While there is high expression of Bcl-XL in the developing and adult brain, few transcriptional control elements have been identified in the bcl-x promoter. There are two functional nuclear factor-kappa B (NF-κB) DNA binding sites clustered upstream of the brain-specific transcription start site in the upstream promoter region of murine bcl-x. Recombinant NF-κB proteins bind to these sites. Also NF-κB overexpression, coupled with bcl-x promoter/reporter assays using a series of murine bcl-x promoter and deletion mutants, has identified the downstream 1.1kb of the bcl-x promoter as necessary for basal promoter activity and induction by NF-κB in support of the hypothesis that NF-κB can act to enhance Bcl-XL expression via highly selective interactions with the bcl-x promoter, where NF-κB binding and promoter activation are dependent on specific DNA binding site sequences and NF-κB protein dimer composition. Hypoxia induces apoptosis in the hippocampus where the NF-κB dimers c-Rel/p50 and p50/p50 bind to the bcl-x promoter NF-κB site.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Cotman, C., Whittemore, E., Watt, J., Anderson, A. J., and Loo, D. 1994. Possible role of apoptosis in Alzheimer's disease. Annu. NY Acad. Sci. 747:36–49.

    Google Scholar 

  2. Thompson, C. 1995. Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462.

    Google Scholar 

  3. Kerr, J., Wyllie, A., and Currie, A. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Brit. J. Cancer 26:239–257.

    Google Scholar 

  4. Sulston, J. and Horvitz, H. 1977. Post-embryonic cell lineages of the nematode Caenorhabditis elegans. Develop. Biol. 82:110–156.

    Google Scholar 

  5. Ellis, H. and Horvitz, H. 1986. Genetic control of programmed cell death in the nematode C. elegans. Cell 44:817–829.

    Google Scholar 

  6. Hengartner, M. and Horvitz, H. 1992. C. elegans gene ced-9 protects cells from programmed cell death. Nature 356:494–499.

    Google Scholar 

  7. Yuan, J., Shaham, S., Ledoux, S., Ellis, H., and Horvitz, H. 1993. The C. elegans death gene ced-3 encodes a protein similar to mammalian interleukin-1-beta-converting enzyme. Cell 75:641–652.

    Google Scholar 

  8. Lazebnik, Y., Kaufmann, S., Desnoyers, S., Poirier, G., and Earnshaw, W. 1994. Cleavage of poly(ADP-ribose)polymerase by a proteinase with properties like ICE. Nature 371:346–347.

    Google Scholar 

  9. Nicholson, D., Ali, A., Thornberry, N., Vaillancourt, J., Ding, C., Gallant, M., Gareau, Y., Griffin, P., Labelle, M., and Lazebnik, Y. 1995. ICE/CED-3 necessary for mammalian apoptosis. Nature 376:37–43.

    Google Scholar 

  10. Xue, D. and Horvitz, H. 1995. Inhibition of the Caenorhabditis elegans cell death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature 377:248–251.

    Google Scholar 

  11. Yuan, J. and Horvitz, H. 1992. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116:309–320.

    Google Scholar 

  12. Zou, H., Henzel, W., Liu, X., Lutschg, A., and Wang, X. 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413.

    Google Scholar 

  13. Tsujimoto, Y. and Croce, C. 1986. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc. Nat. Acad. Sci. USA 83:5214–5218.

    Google Scholar 

  14. Hengartner, M. and Horvitz, H. 1994. C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76:665–676.

    Google Scholar 

  15. Ashkenazi, A. and Dixit, V. 1998. Death Receptors: Signaling and Modulation. Science 281:1305–1308.

    Google Scholar 

  16. Thornberry, N., Rosen, A., and Nicholson, D. 1997. Control of apoptosis by proteases. Adv. Pharmcol. 41:155–177.

    Google Scholar 

  17. Nunez, G., Benedict, M., Hu, Y., and Inohara, N. 1998. Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237–3245.

    Google Scholar 

  18. Alnemri, E., Livingston, D., Nicholson, D., Salveson, G., Thornberry, N., Wong, W., and Yuan, J. 1996. Human ICE/CED-3 protease nomenclature. Cell 87:171.

    Google Scholar 

  19. Walker, N., Talanian, R., Brady, K., Dang, L., Bump, N., Ferenz, C., Franklin, S., Ghayur, T., Hackett, M., Hammill, L., Herzog, L., Hugunin, M., Houy, W., Mankovich, J., Mc-Guiness, L., Orlewicz, E., Paskind, M., Pratt, C., Reis, P., Summani, A., Terranova, M., Welch, J., Xiong, L., Moller, A., Tracey, D., Kamen, R., and Wong, W. 1994. Crystal structure of the cysteine protease interleukin-1-beta-converting enzyme: a (p20/p10)2 homodimer. Cell 78:342–352.

    Google Scholar 

  20. Wilson, K., Black, J.-A., Thomson, J., Kim, E., Griffith, J., Navia, M., Murcko, M., Chambers, S., Aldape, R., Raybuck, S., and Livingston, D. 1994. Structure and mechanism of interleukin-1-beta-converting enzyme. Nature 370:270–275.

    Google Scholar 

  21. Rotonda, J., Nicholson, D., Fazil, K., Gallant, M., Gareau, Y., Labelle, M., Peterson, E., Rasper, D., Ruel, R., Vaillancourt, J., Thornberry, N., and Becker, J. 1996. The three dimensional structure of apopain/CPP32, a key mediator of apoptosis. Nature Struct. Biology 3:619–625.

    Google Scholar 

  22. Cohen, G. 1997. Caspases: the executioners of apoptosis. Biochem. J. 326:1–16.

    Google Scholar 

  23. Xue, D. and Horvitz, H. 1997. Caenorhabditis elegans CED-9 is a bifunctional cell death inhibitor. Nature 377:248–251.

    Google Scholar 

  24. Cheng, E., Kirsch, D., Clem, R., Ravi, R., Kastan, M., Bedi, A., Ueno, K., and Hardwick, J. 1997. Conversion of Bcl-2 to a Bax-like Death Effector by Caspases. Science 278:1966–1968.

    Google Scholar 

  25. Clem, R., Cheng, E., Karp, C., Kirsch, D., Ueno, K., Takahashi, A., Kastan, M., Griffin, D., Earnshaw, W., Veliuona, M., and Hardwick, J. 1998. Modulation of cell death by Bcl-XL through caspase interaction. Proc. Nat. Acad. Sci. 95:554–559.

    Google Scholar 

  26. Widmann, C., Gibson, S., and Johnson, G. 1998. Caspasedependent cleavage of signalling proteins during apoptosis: A turn-off mechanism for anti-apoptotic signals. J. Biol. Chem. 273:7141–7147.

    Google Scholar 

  27. Wen, L.-P., Fahrni, J., Troie, S., Guan, J.-L., Orth, K., and Rosen, G. 1997. Cleavage of focal adhesion kinase by caspases during apoptosis. J. Biol. Chem. 272:26056–26061.

    Google Scholar 

  28. Rao, L., Perez, D., and White, E. 1996. Lamin proteolysis facilitates nuclear events during apoptosis. J. Cell Biol. 135:1441–1455.

    Google Scholar 

  29. Brancolini, C., Benedetti, M., and Schneider, C. 1995. Microfilament reorganization during apoptosis: The role of Gas2, a possible substrate for ICE-like proteases. EMBO J. 14:5179–5190.

    Google Scholar 

  30. Kothakota, S., Azuma, T., Reinhard, C., Klippel, A., Tang, J., Chu, K., TJ, M., Kirschner, M., Koths, K., Kwiatkowski, D., and Williams, L. 1997. Caspase-3-generated fragment of gelsolin: Effector of morhological change in apoptosis. Science 278:294–298.

    Google Scholar 

  31. Cryns, V., Bergeron, L., Zhu, H., Li, H., and Yuan, J. 1996. Specific cleavage of alpha-fodrin during fas-and TNF-induced apoptosis is mediated by an interleukin-1-beta-converting enzyme/ced-3 protease distinct from the poly(ADP ribose)polymerase protease. J. Biol. Chem. 271:31277–31282.

    Google Scholar 

  32. Sakahira, H., Enari, M., and Nagata, S. 1998. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391:96–99.

    Google Scholar 

  33. Chinnaiyan, A., O'Rourke, K., Yu, G.-L., Lyons, R., Garg, M., Duan, D., Xing, L., Gentz, R., Ni, J., and Dixit, V. 1996. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science 274:990–992.

    Google Scholar 

  34. Chinnaiyan, A., O'Rourke, K., Tewari, M., and Dixit, V. 1995. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512.

    Google Scholar 

  35. Hsu, H., Xiong, J., and Goeddel, D. 1995. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 81:495–504.

    Google Scholar 

  36. Muzio, M., Chinnaiyan, A., Kischkel, F., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J., Zhang, M., Gentz, R., Mann, M., Kreammer, P., Peter, M., and Dixit, V. 1996. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death inducing signaling complex. Cell 85:817–827.

    Google Scholar 

  37. Martin, D., Siegel, R., Zheng, L., and Lenardo, M. 1998. Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHa1) death signal. J. Biol. Chem. 273:4345–4349.

    Google Scholar 

  38. Muzio, M., Stockwell, B., Salvesen, G., and Dixit, V. 1998. An induced proximity model for caspase-8 activation. J. Biol. Chem. 273:2926–2930.

    Google Scholar 

  39. Fernandez-Alnemri, T., Armstrong, R., Krebs, J., Srinivasula, S., Wang, L., Bullrich, F., Fritz, L., Trapani, J., Tomaselli, K., Litwack, G., and Alnemri, E. 1996. In vitro activation of CPP32 and Mch3 by Mch4, a novel humna apoptotic cysteine protease containing two FADD-like domains. Proc. Nat. Acad. Sci. USA 93:7464–7469.

    Google Scholar 

  40. Liu, X., Kim, C., Yang, J., Jemmerson, R., and Wang, X. 1996. Induction of apoptotic program in cell-free extracts: Requirement for dATP and cytochrome c. Cell 86:147–157.

    Google Scholar 

  41. Li, P., Nijhawan, D., I, B., Srinivasula, S., Ahmad, M., Almeri, E., and Wang, X. 1997. Cytochrome C and dATP-dependent formation of Apaf-1/caspase-9 initiates an apoptotic protease cascade. Cell 91.

  42. Zou, H., Li, Y., and Wang, X. 1999. An APAF-1-cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 274:11549–11556.

    Google Scholar 

  43. Zoratti, M. and Szabo, I. 1995. The mitochondrial permiability transition. Biochem. Biophys. Acta 1241:139–176.

    Google Scholar 

  44. Bernardi, P. and Petronilli, V. 1996. The permiability transition pore as a mitochondrial calcium release channel: a critical appraisal. J. Bioenerg. Biomem. 28:129–136.

    Google Scholar 

  45. Beutner, G., Riede, B., Welte, W., and Brdiczka, D. 1996. Complexes between kinases, mitochondrial porin, and adenylate translocator in rat brain resemble the permiability transition pore. FEBS Lett. 396:189–195.

    Google Scholar 

  46. Brustovetsky, N. and Klingenberg, M. 1996. Mitochondrial ADP/ATP can be reversably converted into a large channel by Ca2+. Biochemistry 35:8483–8488.

    Google Scholar 

  47. Vayssiere, J.-L., Petit, P., Risler, Y., and Mignotte, B. 1994. Commitment to apoptosis is associated with changes in mitochondrial biogenesis and activity in cell lines conditionally immortalized with simian virus 40. Proc. Nat. Acad. Sci. USA 91:11752–11756.

    Google Scholar 

  48. Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssiere, J.-L., Petit, P., and Kroemer, G. 1995. Reduction in mitochondrial potential constitutes an early irreversable step in programmed lymphocyte death in vivo. J. Exp. Med. 181:1161–1172.

    Google Scholar 

  49. Marchetti, P., Castedo, M., Susin, S., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskins, M., and Kroemer, G. 1996. Mitochondrial permiability transition is a central coordinating event of apoptosis. J. Exp. Med. 184:1155–1160.

    Google Scholar 

  50. Vander Heiden, M., Chandel, N., Schumacker, P., and Thompson, C. 1999. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol. Cell 3:159–167.

    Google Scholar 

  51. Korsmeyer, S. 1992. Bcl-2 initiates a new catagory of oncogenes: Regulators of cell death. Blood 80:879–886.

    Google Scholar 

  52. Bahkshi, A., Jenson, J., Goldman, P., Wright, J., McBride, O., Epstein, A., and Korsmeyer, S. 1985. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41:899–906.

    Google Scholar 

  53. Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E., and Croce, C. 1985. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229:1390–1393.

    Google Scholar 

  54. Cleary, M., Smith, S., and Sklar, J. 1986. Cloning and structural analysis of cDNAs for bcl-2, and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47:19–28.

    Google Scholar 

  55. Graninger, W., Seto, M., Boutain, B., Goldman, P., and Korsmeyer, S. 1987. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J. Clin. Invest. 80:1512–1515.

    Google Scholar 

  56. Nunez, G., London, L., Hockenbery, D., Alexander, M., Mc-Kearn, J., and Korsmeyer, S. 1990. Deregulated Bcl-2 expression selectively prolongs survival of growth factor-deprived hematopoietic cell lines. J. Immunol. 144:3602–3610.

    Google Scholar 

  57. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R., and Korsmeyer, S. 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336.

    Google Scholar 

  58. Boise, L., Gonzalez-Garcia, M., Postema, C., Ding, L., Lindsten, T., Turka, L., Mao, X., Nunez, G., and Thompson, C. 1993. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic c-ell death. Cell 74:597–608.

    Google Scholar 

  59. Boyd, J., Gallo, G., Elangovan, B., Houghton, A., Malstrom, S., Avery, B., Ebb, R., Subramanian, T., Chittenden, T., Lutz, R., and Chinnadurai, G. 1995. Bik, a novel death-inducing protein shares a distinct motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene 11:1921–1928.

    Google Scholar 

  60. Chittenden, T., Harrington, E., O'Connor, R., Flemminton, C., Lutz, R., Evan, G., and Guild, B. 1995. Induction of apoptosis by the Bcl-2 homolog Bak. Nature 374:733–736.

    Google Scholar 

  61. Yang, E., Zha, J., Jockel, J., Boise, L., Thompson, C., and Korsmeyer, S. 1995. Bad, a heterodimeric partner of Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291.

    Google Scholar 

  62. Gibson, L., Holmgreen, S., Huang, D., Bernard, O., Copeland, N., Jenkins, N., Sutherland, G., Baker, E., Adams, J., and Cory, S. 1996. Bcl-w, A novel member of the bcl-2 family, promotes cell survival. Oncogene 13:665–675.

    Google Scholar 

  63. Wang, K., Yin, X., Chao, D., Milliman, C., and Korsmeyer, S. 1996. BID: a novel BH3 domain-only death agonist. Genes Dev. 10:2859–2869.

    Google Scholar 

  64. Sattler, M., Liang, H., Nettesheim, D., Meadows, R., Harlan, J., Eberstadt, M., Yoon, H., Shuker, S., Chang, B., Minn, A., Thompson, C., and Fesik, S. 1997. Structure of Bcl-x(L)-Bak peptide complex-recognition between regulators of apoptosis. Science 275:983–986.

    Google Scholar 

  65. Oltvai, Z., Milliman, C., and Korsmeyer, S. 1993. Bcl-2 Heterodimerizes In Vivo with a Conserved Homolog, Bax, That Accelerates Cell Death. Cell 74:609–619.

    Google Scholar 

  66. Zha, J., Harada, H., Osipov, K., Jockel, J., Waksman, G., and Korsmeyer, S. 1996. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3-not Bcl-xL. Cell 87:619–628.

    Google Scholar 

  67. Ito, T., Deng, X., Carr, B., and May, W. 1997. Bcl-2 Phosphorylation Required for Anti-apoptosis Function. J. Biol. Chem. 272:11671–11673.

    Google Scholar 

  68. Gross, A., Yin, X.-M., Wang, K., Wei, M., Jockel, J., Milliman, C., Erdjument-Bromage, H., Tempst, P., and Korsmeyer, S. 1999. Caspase Cleaved BID Targets Mitochondria and is required for Cytochrome c Release, while Bcl-xL Prevents This Release but Not Tumor Necrosis Factor-R1/Fas Death. J. Biol. Chem. 274:1156–1163.

    Google Scholar 

  69. Hsu, Y.-T., Wolter, K., and Youle, R. 1997. Cytosol-to-membrane redistribution of Bax and Bcl-xL during apoptosis. Proc. Natl. Acad. Sci. USA 94:3668–3672.

    Google Scholar 

  70. Wolter, K., Hsu, Y., Smith, C., Nechushtan, A., Xi., X., and Youle, R. 1997. Movement of Bax from the cytosol to the mitochondria during apoptosis. J. Cell Biol. 139:1281–1292.

    Google Scholar 

  71. Gonzalez-Garcia, M., Perez-Ballestero, R., Ding, L., Duan, L., Boise, L., Thompson, C., and Nunez, G. 1994. Bcl-xL is the major bcl-x mRNA from expressed during murine development and its product localizes to mitochondria. Development 120:3033–3042.

    Google Scholar 

  72. Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Martinou, I., Bernasconi, L., Bernard, A., Mermod, J.-J., Mazzei, G., Maundrell, K., Gambale, F., Sadoul, R., and Martinou, J.-C. 1997. Inhibition of Bax channel-forming activity by Bcl-2. Science 277:370–372.

    Google Scholar 

  73. Minn, A., Velez, P., Schendel, S., Liang, H., Muchmore, S., Fesik, S., Fill, M., and Thompson, C. 1997. Bcl-x(l) forms an ion channel in synthetic lipid membranes. Nature 385:353–357.

    Google Scholar 

  74. Schendel, S., Xie, Z., Montal, M., Matsuyama, S., Montal, M., and Reed, J. 1997. Channel formation by antiapoptotic protein Bcl-2. Proc. Natl. Acad. Sci. USA 94:5113–5118.

    Google Scholar 

  75. Schlesinger, P., Gross, A., Yin, X., Yamamoto, K., Saito, M., Waksman, G., and Korsmeyer, S. 1997. Comparison of the ion channel activity of pro-apoptotic BAX and anti-apoptotic BCL-2. Proc. Natl. Acad. Sci. USA 94:357–362.

    Google Scholar 

  76. Jurgensmeier, J., Xie, Z., Devereux, Q., Ellerby, L., Bredesen, D., and Reed, J. 1998. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA 95:4997–5002.

    Google Scholar 

  77. Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J., Susin, S., Vieira, H., Prevost, M.-C., Xie, Z., Matsuyama, S., Reed, J., and Kroemer, G. 1998. Bax and adenine nucleotide translocator cooperate in the mitochondria control of apoptosis. Science 281:2027–2031.

    Google Scholar 

  78. Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R., Matsuda, H., and Tsujimoto, Y. 1998. Bax interacts with the permiability transition pore to induce permiability transition and cytochrome c release in isolated mitochondria. Proc. Natl. Acad. Sci. USA 95:14681–14686.

    Google Scholar 

  79. Shimizu, S., Eguchi, Y., Kamike, W., Funahashi, Y., Mignon, A., Lacronique, V., Matsuda, H., and Tsujimoto, Y. 1998. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc. Natl. Acad. Sci. USA 95:1455–1459.

    Google Scholar 

  80. Shimizu, S., Narita, M., and Tsujimoto, Y. 1999. Bcl-2 family proteins regulate the release of cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487.

    Google Scholar 

  81. Finucane, D., Bossy-Wetzel, E., Waterhouse, N., Cotter, T., and Green, D. 1999. Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J. Biol. Chem. 274:2225–2233.

    Google Scholar 

  82. Gonzalez-Garcia, M., Garcia, I., Ding, L., O'shea, S., and Boise, L. 1995. Bcl-x is expressed in embryonic and postnatal neural tissues and functions to prevent cell death. Proc. Natl. Acad. Sci. USA 92:4304–4308.

    Google Scholar 

  83. Motoyama, N., Wang, F., Roth, K., Sawa, H., and Nakayama, K.-I. 1995. Masive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510.

    Google Scholar 

  84. Chao, D. and Korsmeyer, S. 1998. Bcl-2 Family: Regulators of cell death. Annu. Rev. Immunol. 16:395–419.

    Google Scholar 

  85. Hu, Y., Benedict, M., Wu, D., Inohara, N., and Nunez, G. 1998. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1 dependent caspase-9 activation. Proc. Natl. Acad. Sci. USA 95:4386–4391.

    Google Scholar 

  86. Pan, G., O'Rourke, K., and Dixit, V. 1998. Caspase-9, Bcl-XL, and Apaf-1 Form a Ternary Complex. J. Biol. Chem. 273:5841–5845.

    Google Scholar 

  87. Sen, R. and Baltimore, D. 1986. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716.

    Google Scholar 

  88. Beg, A., Sha, W., Bronson, R., Ghosh, S., and Baltimore, D. 1995. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170.

    Google Scholar 

  89. Sonenshein, G. 1997. Rel/NF-kappa B transcription factors and the control of apoptosis. Seminars in Cancer Biol. 8:113–119.

    Google Scholar 

  90. Schmid, R., Perkins, N., Duckett, C., Andrews, P., and Nabel, G. 1991. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature 352:733–736.

    Google Scholar 

  91. Bours, V., Burd, P., Brown, K., J, V., Park, S., Ryseck, R.-P., Bravo, R., Kelly, K., and Siebenlist, U. 1992. A novel mitogeninducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site. Mol. Cell. Biol. 12:685–695.

    Google Scholar 

  92. Mercurio, F., Didonato, J., Rosette, C., and Karin, M. 1992. Molecular cloning and characterization of a novel Rel/NFkappa B family member displaying structural and functional homology to NF-kappa B p50/p105. DNA and Cell Biol. 11:523–537.

    Google Scholar 

  93. Bours, V., Villalobos, J., Burd, P., Kelly, K., and Siebenlist, U. 1990. Cloning of a mitogen-inducible gene encoding a kappa B DNA-binding protein with homology to the rel oncogene and to cell-cycle motifs. Nature 348:76–80.

    Google Scholar 

  94. Ghosh, S., Gifford, A., Riviere, L., Tempst, P., Nolan, G., and Baltimore, D. 1990. Cloning of the p50 DNA binding subunit of NF-kappa B; homolgy to rel and dorsal. Cell 62.

  95. Kieran, M., Blank, V., Logeat, F., Vandekerckhove, J., Lottspeich, F., Le Bail, O., Urban, M., Kourilsky, P., Baeuerle, P., and Israel, A. 1990. The DNA-binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell 62:1007–1018.

    Google Scholar 

  96. Nolan, G., Ghosh, S., Liou, H.-C., Tempst, P., and Baltimore D. 1991. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell 64:961–969.

    Google Scholar 

  97. Ruben, S. M., Dillon, P. J., Schreck, R., Henkel, T., Chen, C.-H., Maher, M, Baeurle, P. A., and Rosen, C. A. 1991. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kB. Science 251:1490–1493.

    Google Scholar 

  98. Brownell, E., Mittereder, N., and Rice, N. 1989. A human rel proto-oncogene cDNA containing an Alu fragment as a potential coding exon. Oncogene 4:935–942.

    Google Scholar 

  99. Ryseck, R.-P., Bull, P., Takamiya, M., Bours, V., Siebenlist, U., Dobrzanski, P., and Bravo, R. 1992. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol. Cell. Biol. 12:674–684.

    Google Scholar 

  100. Liou, H.-C. and Baltimore, D. 1993. Regulation of the NFkappa B/rel transcription factor and I kappa B inhibitor system. Curr. Op. Cell Biol. 5:477–487.

    Google Scholar 

  101. Bours, V., Franzoso, G., Azarenko, V., Park, S., Kanno, T., Brown, K., and Siebenlist, U. 1993. The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers. Cell 72:729–739.

    Google Scholar 

  102. Ghosh, S. and Baltimore, D. 1990. Activation in vitro of NFkappa B by phosphorylation of its inhibitor, I kappa B. Nature 344:678–682.

    Google Scholar 

  103. Link, E., Kerr, L., Schreck, R., Zabel, U., Verma, I., and Baeuerle, P. 1992. Purified I kappa B beta is inactivated upon dephosphorylation. J. Biol. Chem. 267:239–246.

    Google Scholar 

  104. Whiteside, S., Epinat, J., Rice, N., and Israel, A. 1997. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel activity. EMBO J. 16:1413–1426.

    Google Scholar 

  105. Inoue, J., Kerr, L., Kakizuka, A., and Verma, I. 1992. I kappa B gamma, a 70 kd protein identical to the c-terminal half of p110 NF-kappa B: A new member of the I kappa B family. Cell 68:1109–1120.

    Google Scholar 

  106. Beg, A., Ruben, S., Scheinman, R., Haskill, S., Rosen, C., and Baldwin, A. J. 1992. I kappa B interacts with the nuclear localization sequences of the subunits of NF-kappa B: a mechanism for cytoplasmic retention. Genes Dev. 6:1899–1913.

    Google Scholar 

  107. Rice, N., MacKichen, M., and Israel, A. 1992. The precurser to NF-kappa B p50 has I kappa B-like functions. Cell 71:243–253.

    Google Scholar 

  108. Chen, Z., Parent, L., and Maniatis, T. 1996. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination dependent protein kinase activity. Cell 84:853–862.

    Google Scholar 

  109. Mercurio, F., Zhu, H., Murray, B., Shevchenko, A., Bennet, B., Li, J., Young, D., Barbosa, M., Mann, M., and Rao, A. 1997. IKK-1 and IKK-2: Cytokine-activated I kappa B kinases essential for NF-kappa B activation. Science 278:860–866.

    Google Scholar 

  110. Woronicz, J., Gao, X., Cao, Z., Rothe, M., and Goeddel, D. 1997. I kappa B kinase-beta: NF-kappa B activation and complex formation with I kappa B kinase-alpha and NIK. Science 278:866–869.

    Google Scholar 

  111. Zandi, E., Chen, Y., and Karin, M. 1998. Direct phosphorylation of I kappa B by IKK-alpha and IKK-beta: discrimination between free and NF-kappa B bound substrate. Science 281:1360–1363.

    Google Scholar 

  112. Beg, A., Finco, T., Nantermet, P., and Jr., B. A. 1993. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol. Cell. Biol. 13:3310–3310.

    Google Scholar 

  113. Mellitis, K., Hay, R., and Goodbourn, S. 1993. Proteolytic degradation of MAD-3 (I kappa B alpha) and enhanced processing of the NF kappa B precursor p105 are obligatory steps in activation of NF-kappa B. Nucleic Acids Res. 21:5059–5066.

    Google Scholar 

  114. Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A., Anderson, J., Mann, M., Mercurio, F., and Ben-Neriah, Y. 1998. Identification of the receptor component of the I kappa B alpha-ubiquitin ligase. Nature 396:590–594.

    Google Scholar 

  115. Palombella, V., Rando, O., Golberg, A., and Maniatis, T. 1994. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 78:773–785.

    Google Scholar 

  116. Didonato, J., Mercurio, F., and Karin, M. 1995. Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol. Cell. Biol. 15:1302–1311.

    Google Scholar 

  117. Torgerson, T., Colosia, A., Donahue, J., Lin, Y.-Z., and Hawiger, J. 1998. Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear transport in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50. J. Immunol. 161:6084–6092.

    Google Scholar 

  118. Muller, J., Ziegler-Heitbrock, H., and Baeuerle, P. 1993. Nuclear Factor kappa B, a mediator or Lipopolysaccaride Effects. Immunobiol. 187:233–256.

    Google Scholar 

  119. Beg, A. A. and Baltimore, D. 1996. An essential role for NFkB in preventing TNF-a-induced cell death. Science. 274:782–784.

    Google Scholar 

  120. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D., and Verma, I. M. 1996. Suppression of TNF-α-induced apoptosis by NF-κB. Science 274:787–789.

    Google Scholar 

  121. Wu, M., Lee, H., Bellas, R., Schauer, S., Arsura, M., Katz, D., Fitzgerald, M., Rothstein, T., Sherr, D., and Sonenshein, G. 1996. Inhibition of NF-kappa B/Rel induces apoptosis of murine B cells. EMBO J. 15:4682–4690.

    Google Scholar 

  122. Lezoualc'h, F., Sagara, Y., Holsboer, F., and Behl, C. 1998. High Constitutive NF-kappa B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells. J. Neurosci. 18:3224–3232.

    Google Scholar 

  123. Clemens, J., Stephenson, D., Yin, T., Smalstig, E., Panetta, J., and Little, S. 1998. Drug-induced neuroprotection from global ischemia is assosiated with prevention of persistent but not transient activation of Nuclear Factor kappa B in rats. Stroke 29:677–682.

    Google Scholar 

  124. Wu, H. and Lozano, G. 1994. NF-kappa B Activation of p53. J. Biol. Chem. 269:20067–20074.

    Google Scholar 

  125. Wang, C.-Y., Mayo, M., Korneluk, R., Goeddel, D., and Baldwin, A. 1998. NF-kappa B Antiapoptosis: Induction of TRAF1 and TRAF2 and cIAP1 and cIAP2 to Supress Caspase-8 Activation. Science 281:1680–1683.

    Google Scholar 

  126. Wu, M., Ao, Z., Prasad, K., Wu, R., and Schlossman, S. 1998. IEX-1L, an Apoptosis Inhibitor Involved in NF-kappa BMediated Cell Survival. Science 281:998–1001.

    Google Scholar 

  127. Foo, S. and Nolan, G. 1999. NF-kappa B to the rescue; RELs, apoptosis, and cellular transformation. TIG 15:229–235.

    Google Scholar 

  128. Lee, H., Dadgostar, H., Cheng, Q., Shu, J., and Cheng, G. 1999. NF-kappa B mediated up-regulation of Bcl-x and Bfl-I/A1 is required for CD40 survival signaling in B lymphocytes. Proc. Natl. Acad. Sci. USA 96:9136–9141.

    Google Scholar 

  129. Glasgow, J. N., Wood, T., and Perez-Polo 2000. Identification and characterization of NF-κB binding sites in the murine bcl-x promoter. J. Neurochem. 75:1377–1389.

    Google Scholar 

  130. Hettmann, T., Didonato, J., Karin, M., and Leiden, J. 1999. An Essential Role for NF-kappa B in Promoting Double Positive Thymocyte Apoptosis. J. Exp. Med. 189:145–157.

    Google Scholar 

  131. Tamatani, M., Che, Y., Matsuzaki, H., Ogawa, S., Okado, H., Miyake, S., Mizuno, T., and Tohyama, M. 1999. Tumor Necrosis Factor Induces Bcl-2 and Bcl-x Expression through NF-kappa B Activation in Primary Hippocampal Neurons. J. Biol. Chem. 274:8531–8538.

    Google Scholar 

  132. Dixon, E., Stephenson, D., Clemens, J., and Little, S. 1997. Bcl-Xshort is elevated following severe global ischemia in rat brains. Brain Res. 776:222–229.

    Google Scholar 

  133. Saikumar, P., Dong, Z., Weinberg, J. M., and Venkatachalam, M. A. 1998. Mechanisms of cell death in hypoxia/reoxygenation injury. Oncogene 17:3341–3349.

    Google Scholar 

  134. Scott, R. J. and Hegyi, L. 1997. Cell death in perinatal hypoxicischaemic brain injury. Neuropath. Appl. Neurobiol. 23:307–314.

    Google Scholar 

  135. Pulera, M. R., Adams, L. M., Liu, H., Santos, D. G., Nishimura, R. N., Yang F., Cole G. M., and Wasterlain, C. G. 1998. Apoptosis in a neonatal rat model of cerebral hypoxia-ischemia. Stroke 29:2622–2630.

    Google Scholar 

  136. Charriaut-Marlangue, C., Margaill, I., Represa, A., Popovici, T., Plotkine, M., and Ben-Ari, Y., 1996. Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J. Cereb. Blood Flow Metab. 16:186–194.

    Google Scholar 

  137. Piantadosi, C. A., Zhang, J., and Demchenko, I. T. 1997. Production of hydroxyl radical in the hippocampus after CO hypoxia or hypoxic hypoxia in the rat. Free Rad. Biol. Med. 22:725–732.

    Google Scholar 

  138. Schmidt-Kastner, R., Fliss, H., and Hakim, A. M. 1997. Subtle neuronal death in striatum after short forebrain ischemia in rats detected by in situ end labeling for DNA damage. Stroke 28:163–170.

    Google Scholar 

  139. Kent, T. A., Quast, M., Taglialatela, G., Rea, C., Wei, J., Tao, Z., and Perez-Polo, J. R. 1999. Effect of NGF treatment on outcome measures in a rat model of middle cerebral artery occlusion. J. Neurosci. Res. 55:357–369.

    Google Scholar 

  140. Lin, Y. and Greysen, G. 1996. Analysis of the risk of brain damage in asphyxiated infants. J. Perinat. Med. 24:581–589.

    Google Scholar 

  141. Naulty, C. M., Long, L. B., and Pettett G. 1994. Prevalence of prematuarity low birthweight, and asphyxia as perinatal risk factors in a current population of children with cerebral palsy. Am. J. Perinatol. 11:377–381.

    Google Scholar 

  142. Patel, J. and Edwards, A. D. 1997. Prediction of outcome after perinatal asphyxia. Curr. Opin. Pediatr. 9:128–132.

    Google Scholar 

  143. Volpe, J. J. 1995. Hypoxic-ischemic encephalogpathy: intrauterine assessment. In: Neurology of the newborn. Pp260–278. WBSaunders Co. Philadelphia.

    Google Scholar 

  144. Seidl, R., Stockler-Ipsiroglu, S., Rolinski, B., Kohlhauser, C., Herner, K. R., Lubec, B., and Lubec, G. 2000. Energy metabolism in graded perinatal asphyxia of the rat. Life Sci. 67:421–435.

    Google Scholar 

  145. Cooper, C. E. 1999. In vivo measurements of mitochondiral function and cell death following hypoxic/ischaemic damage to the new-born brain. Biochem. Soc. Symp. 66:123–140.

    Google Scholar 

  146. Clawson, T. F., Vannucci, S. J., Wang, M. G., Seaman, L. B., Yang, X. L., and Lee, W. H. 1999. Hypoxia-ischemia-induced apoptotic cell death correlates with IGF-I mRNA decrease in neonatal rat brain. Biol. Sig. Rec. 8:281–293.

    Google Scholar 

  147. Vannucci, R. C., Connor, J. R., Mauger, D. T., Palmer, C., Smith, M. B., Towfighi, J., and Vannucci, S. J. 1999. Rat model of perinatal hypoxic-ischemic brain damage. [Review] J. Neurosci. Res. 55:158–163.

    Google Scholar 

  148. Barth, A., Bauer, R., Gedrange, T., Walter, B., Klinger, W., and Zwiener, U. 1998. Influence of hypoxia and hypoxia/hypercapnia upon brain and blood peroxidative and glutathione status in normal weight and growth-restricted newborn piglets. Exp. Tox. Path. 50:402–410.

    Google Scholar 

  149. Nedelcu, J., Klein, M. A., Aguzzi, A., Boesiger, P., and Martin, E. 1999. Biphasic edema after hypoxic-ischemic brain injury in neonatal rats reflects early neuronal and late glial damage. Pediatr. Res. 46:297–304.

    Google Scholar 

  150. Barkovich, A. J., Baranski, K., Vigneron, D., Partridge, J. C., Hallam, D. K., Hajnal, B. L., and Ferriero, D. M. 1999. Proton MR spectroscopy for the evaluation of brain injury in asphyxiated, term neonates. Am. J. Neurorad. 20:1399–1405.

    Google Scholar 

  151. Thornton, J. S., Ordidge, R. J., Penrice, J., Cady, E. B., Amess, P. N., Punwani, S., Clemence, M., and Wyatt, J. S. 1998. Temporal and anatomical variations of brain water apparent diffusion coeeficient in perinatal cerebral hypoxic-ischemic injury: relationships to cerebral energy metabolism. Mag. Res. Med. 39:920–927.

    Google Scholar 

  152. Delivoria-Papadopoulos, M. and Mishra, O. P. 1998. Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention. [Review] J. Pediatr. 132:S30–34.

    Google Scholar 

  153. Wang, Z. F., Xue, C. S., Zhou, Q. X., Wan, Z. B., and Luo, Q. S. 1999. Effects of tetrandrine on changes of NMDA receptor channel in cortical neurons of rat induced by anoxia. Zhongguo Yao Li Xue Bao 20:729–732.

    Google Scholar 

  154. Volpe, J. J. 1998. Neurologic outcome of prematurity. Arch Neurol. 55:297–300.

    Google Scholar 

  155. Carro, E., Senaris, R. M., Mallo, F., and Dieguez, C. 1998. Inhibin suppresses in vivo growth hormone secretion. Neuroendocrinol. 68:293–296.

    Google Scholar 

  156. Gozal, E., Simakajomboon, N., and Gozal, D. 1998. NF-KB induction during in vivo hypoxia in dorsocaudal brain stem of rateffect of MK-801 and L-NAME. J. Appl. Physiol. 85:372–376.

    Google Scholar 

  157. Carter, B. D., Kaltschmidt, C., Kaltschmidt, B., Offenhauser, N., Böhm-Matthaei, R., Baeuerle, P., and Barde, Y.-A. 1996. Selective activation of NF B by nerve growth factor through the neurotrophin receptor p75. Science 272:542–545.

    Google Scholar 

  158. Taglialatela, G., Kauffman, J. A., Trevino, A., and Perez-Polo, J. R. 1998. Central Nervous System DNA fragmentation induced by the inhibition of nuclear factor Kappa B. NeuroReport 9:489–493.

    Google Scholar 

  159. Flohe, L., Brigelius-Flohe, R., Saliou, C. Traber, M. G., and Packer, L. 1997. Redox Regulation of NF-Kappa B action. Free Rad. Biol. Med. 22:1115–1126.

    Google Scholar 

  160. Zhang, S., Tobaru, T., Zivin, J. A., and Shackelford, D. A. 1998. Activaiton of nuclear factor-κB in the rabbit spinal cord followingischemia and reperfusion. Mol. Brain Res. 63:121–132.

    Google Scholar 

  161. Franzoso, G., Bours, V., Azarenko, V., Park, S., Tomita-Yamaguchi, M., Kanno, T., Brown, K., and Siebenlist, U. 1993. The oncoprotein Bcl-3 can facilitate NF-kappa B-mediated transactivation by inhibiting p50 homodimers from select kappa B sites. EMBO J. 12:3893–3901.

    Google Scholar 

  162. Fujita, T., Nolan, G. P., Liou, H. C., Scott, M. L., and Baltimore, D. 1993. The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that acts through NF-kappa B p 50 homodimers. Genes Dev. 7:1354–1363.

    Google Scholar 

  163. Nolan, G. P., Fujita, K., Huppi, C., Liou, H. C., Scott, M. L., and Baltimore, D. 1993. The bcl-3 proto-oncogene encodes a nuclear I kappa B-like molecule that protects and interacts with NF-kappa B p50 and p52 in a phosphorylation-dependent manner. Mol. Cell Biol. 13:3557–3566.

    Google Scholar 

  164. Bundy, D. L. and McKeithan, T. W. 1997. Diverse effects of Bcl 3 phosphorylation on its modulation of NF-kappaB p50 homodimer binding to DNA. J. Biol. Chem. 272:33132–33139.

    Google Scholar 

  165. Bohuslav, J., Kravchenko, V. V., Parry, G. C., Erlich, J. H., Gerondakis, S., Mackman, N., and Ulevitch, R. J. 1998. J. Clin. Invest. 102:1645–1652.

    Google Scholar 

  166. Watanabe, N., Iwamura, T., Shinoda, T., and Fujita, T. 1997. Regulation of NFKB1 proteins by the candidate oncoprotein BCL-3: generated kappaB homodimers from the cytoplasmic pool of p50–p105 and nuclear transcription factor. EMBO J. 16:3609–3620.

    Google Scholar 

  167. Na, S. Y., Choi, J. E., Kim, H. J., Jhun, B. H., Lee, Y. C., and Lee, J. W. 1999. J. Biol. Chem. 274:28491–28496.

    Google Scholar 

  168. Siebenlist, U., Frazoso, G., and Brown, K. 1994. Structure, regulation and function of NF-κB. Ann. Rev. Cell Bio. 10:405–455.

    Google Scholar 

  169. Heissmeyer, V., Krappmann, D., Wulczyn, F. G., and Scheidereit, C. 1999. NF-kappaB p105 is a target of IkappaB kinases and controls signal induction of p50 complexes. EMBO J. 18:4766–4778.

    Google Scholar 

  170. Rebollo, A., Dumoutier, L., Renauld, J. C., Zaballos, A., Ayllon, V., and Martinez, A. C. 2000. Bcl-3 expression promotes cell survival following interleukin-4 deprivation controlled by AP1 and AP1-like transcription factors. Mol. Cell Biol. 20:3407–3416.

    Google Scholar 

  171. Isenmann, S., Stoll, G., Schroeter, M., Krajewski, S., Reed, J. C., and Baerh, M. 1998. Differential regulation of Bax, Bcl-2, and Bcl-x proteins in focal cortical ischemia in the rat. Br. Pathol. 8:49–62.

    Google Scholar 

  172. Parsadanian, A. S., Cheng, Y., Keller-Peck, C. R., Holtzman, D. M., and Snider, W. D. 1998. Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons. J. Neurosci. 18:1009–1019.

    Google Scholar 

  173. Lou, J., Lenke, L. G., Xu, F., and O'Brien, M. 1998. In vivo Bcl-2 oncogene neuronal expression in the rat spinal cord. Spine 23:517–523.

    Google Scholar 

  174. Martinou, J. C., Dubois-dauphin, M., Staple, J. K., Rodriguez, I., Frankowski, H., Roth, K. A., Motoyama, N., and Loh, D. Y. 1996. Apoptosis of Bcl-xL deficient telencephalic cells in vitro. J. Neurosci. 16:1753–1758.

    Google Scholar 

  175. Li, G. L., Brodin, G., Farooque, M., Funa, K., Holtz, A., Wang, W. L., and Olsson, Y. 1996. Apoptosis and expression of Bcl-2 after compression trauma to rat spinal cord. J. Neuropath. & Exp. Neurol. 55:280–289.

    Google Scholar 

  176. Vogt, M., Bauer, M. K., Ferrari, D., and Schulze-Ostroff, K. 1998. Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO-1/Fas) ligand expression in microglial cells. FEBS Lett. 429:67–72.

    Google Scholar 

  177. Ichiyama, T., Zhao, H., Catania, A., Furukawa, S., and Lipton, J. M. 1999. Alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and experimental brain inflammation. Exp. Neur. 157:359–365.

    Google Scholar 

  178. Kessler, J. A., Ludlam, W. H., Freidin, M. M., Hall, D. H., Michaelson, M. D., Spray, D. C., Dougherty, M., and Batter, D. K. 1993. Cytokine-induced programmed cell death of cultured sympathetic neurons. Neuron 11:1123–1132.

    Google Scholar 

  179. Kitajima, I., Soejima, Y., Taksaki, I., Beppu, H., Tokioka, T., and Maruyama, I. 1996. Ceramide-induced nuclear translocation of NF-κB is a potential mediator of the apoptotic response to TNF-α in murine clonal osteoblasts. Bone 19:263–270.

    Google Scholar 

  180. Lin, K. I., Lee, S. H., Narayanan, R., Baraban, J. R., Hardwick, J. M., and Ratan, R. R. 1995. Thiol agents and bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of NF-κB. J. Cell Biol. 131:1–14.

    Google Scholar 

  181. Grilli, M., Pizzi, M., Memo, M., and Spano, P. 1996. Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science 274:1383–1385.

    Google Scholar 

  182. Clemens, J. A., Stephenson, D. T., Smalstig, E. B., Dixon, E. P., and Little, S. P. 1997. Global ischemia activates nuclear factor kappa B in forebrain neurons of rats. Stroke 28:1073–1080.

    Google Scholar 

  183. Barger, S. W., Horster, D., Furukawa, K., Goodman, Y., Krieglstein, J., and Mattson, M. P. 1995. Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a kB-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc. Natl. Acad. Sci. USA 92:9238–9332.

    Google Scholar 

  184. Barger, S. W. and Mattson, M. P. 1996. Induction of neuroprotective kappa B-dependent transcription by secreted forms of the Alzheimer's beta-amyloid precursor. Mol. Brain Res., 40:116–126.

    Google Scholar 

  185. Goodman, Y. and Mattson, M. P. 1996. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults and amyloid β-peptide toxicity. N. Neurochem. 66:869–872.

    Google Scholar 

  186. Grilli, M. and Memo, M. 1999. Nuclear factor kappa B/Rel proteins: a point of convergence of signaling pathways relevant in neuronal function and dysfunction. Biochem. Pharmacol. 57:1–7.

    Google Scholar 

  187. Kitamura, Y., Shimohama, S., Kamoshima, W., Ota, T., Matsuoka, Y., Nomura, Y., Smith, M. A., Perry, G., Whitehouse P. J., and Taniguchi, T. 1995. 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, 1998.

    Google Scholar 

  188. Boise, H., Gottschalk, A. R., Quintans, J., and Thompson, C. B. Bcl-2 and Bcl-2-related proteins in apoptosis regulation. Curr. Top. Microbiol. Immunol. 200:107–121.

  189. Bredesen, D. 1995. Neural apoptosis. Anal. Neurol. 38:839–851.

    Google Scholar 

  190. Hockenbery, D. M., Oltvai, Z. N., Yin, X.-M., Milliman, C. L., and Korsmeyer, S. J. 1993. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251.

    Google Scholar 

  191. Kiefer, M. C., Brauer, M. J., Powers, V. C., Wu, J. J., Umansky, S. R., Tomei, L. D., and Barr, P. J. 1995. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature 374:736–739.

    Google Scholar 

  192. Krajewski, S., Karjewska, M., and Reed, J. C. 1996. Immunohistochemical analysis of in vivo patterns of Bak expression, a pro-apoptotic member of the Bcl-2 family. Cancer Res. 56:2849–2855.

    Google Scholar 

  193. Su, J. H., Satou, T., Anderson, A. J., and Cotman, C. W. 1996. Up-regulation of Bcl-2 is associated with neuronal DNA damage in Alzheimer's disease. NeuroReport 7:437–440.

    Google Scholar 

  194. Su, J. H., Deng, G., and Cotman, C. W. 1997. Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology. J. Neuropath. Exp. Neurol. 56:86–93.

    Google Scholar 

  195. Maroto, R. and Perez-Polo, J. R. 1997. BCL-2 protein expression in apoptosis: oxidative stress versus serum deprivation in PC12 cells. J. Neurochem. 69:514–523.

    Google Scholar 

  196. Chen, J., Zhu, R. L., Nakayama, M., Kawaguchi, K., Jin, K., Stetler, R. A., Simon, R. P., and Graham, S. H. 1996. Expression of the apoptosis-effector gene, Bax, is up-regulated in vulnerable hippocampal CA1 neurons following global ischemia. J. Neurochem. 67:64–71.

    Google Scholar 

  197. Hara, A., Iwai, T., Niwa, M., Uematsu, T., Yoshimi, N., Tanaka,T., and Mori, H. 1996. Immunohistochemical detection of Bax and Bcl-2 proteins in gerbil hippocampus following transient forebrain ischemia. Br. Res. 711:249–253.

    Google Scholar 

  198. Antonawich, F. J., Krajewski, S., Reed, J. C., and Davis, J. N., 1998. Bcl-x1 Bax interaction after transient global ischemia. J. Cereb. Blood Flow Metab. 18:882–886.

    Google Scholar 

  199. Niwa, M., Hara A., Iwai, T., Sassa, T., Mori, H., and Uematsu, T. 1997. Expression of Bax and Bcl-2 protein in the gerbil hippocampus following transient forebrain ischemia and its modification by phencyclidine. Neurol. Res. 19:629–633.

    Google Scholar 

  200. Gillardon, F., Lenz, C., Waschke, K. F., Krajewski, S., Reed, J. C., Zimmermann, M., and Kuschinsky, W. 1996. Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Mol. Br. Res. 40:254–260.

    Google Scholar 

  201. Honkaniemi, J., Massa, S. M., Breckinridge, M., and Sharp, F. R. 1996. Global ischemia induces apoptosis-associated genes in hippocampus. Mol. Br. Res. 42:79–88.

    Google Scholar 

  202. Ferrer, I., Lopez, E., Blanco, R., Rivera, R., Ballabriga, J., Pozas, E., and Martie, E. 1998. Bcl-2, Bax, and Bcl-x expression in the CA1 area of the hippocampus following transient forebrain ischemia in the adult gerbil. Exp. Brain Res. 121:167–173.

    Google Scholar 

  203. Kessler, J. A., Ludlam, W. H., Freidin, M. M., Hall, D. H., Michaelson, M. D., Spray, D. C., Dougherty, M., and Batter, D. K. 1993. Cytokine-induced programmed cell death of cultured sympathetic neurons. Neuron 11:1123–1132.

    Google Scholar 

  204. Wen, X., Furhman, S., Michaels, G. S., Carr, D. B., Smith, S., Barker, J. L., and Somogyi, R. 1998. Large-scale temporal gene expression mapping of central nervous system development. Proc. Natl. Acad. Sci. USA 95:334–339.

    Google Scholar 

  205. Yu, Z., Zhou, D., Bruce-Keller, A. J., Kindy, M. S., and Mattson, M. P. 1999. Lack of the p50 subunit of nuclear factorkappa B increases the vulnerability of hippocampal neurons to excitotoxic injury. J. Neurosci. 19:8856–8865.

    Google Scholar 

  206. Abbadie, C., Kabrun, N., Bouali, F., Smardova, J., Stehelin, D., Vandenbunder, B., and Enrietto, P. J. 1993. High levels of c-rel expression are associated with programmed cell death in the developing avian embryo and in bone marrow cells in vitro. Cell 75:899–912.

    Google Scholar 

  207. Jung, S., Yaron, A., Alkalay, I., Hatzubai, A., Avraham, A., and Ben-Neriah, Y., 1995. Costimulation requirement for AP-1 and NF-kappa B transcription factor activation in T cells. Ann. NY Acad. Sci. 766:245–252, 1995.

    Google Scholar 

  208. Grilli, M., Pizzi, M., Memo, M., and Spano, P. 1996. Neuroprotection by aspirin and sodium salicylate through blockade of NF-κB activation. Science 274:1383–1385.

    Google Scholar 

  209. Grimm, S., Bauer, M. K. A., Baeuerle, P. A., and Schulze-Osthoff, K. 1996. Bcl-2 down-regulates the activity of transcription factor NF-κB induced upon apoptosis. J. Cell Biol. 134:13–23.

    Google Scholar 

  210. Baichwal, V. R. and Baeuerle, P. A. 1997. Activate NF-kappa B or die? Curr. Biol. 7:R94–96.

    Google Scholar 

  211. Lipton, S. A. 1997. Janus faces of NF-kappa B: neurodestruction versus neuroprotection. Nat. Med. 3:20–22.

    Google Scholar 

  212. Qiu, J.-X., Glasgow, J., Kent, T. A., Rassin, D. K., and Perez-Polo, J. R. 2001. Differential NF-κB regulation of bcl-x gene expression in Hippocampus and basal forebrain in response to hypoxia. J. Neurosci. Res. 64:223–234.

    Google Scholar 

  213. Vaux, D. L. 1993. Toward understanding of the molecular mechanisms of physiological cell death. Proc. Nat. Acad. Sci. USA 90:786–789.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas, 77555-0652

    Joel N. Glasgow, JingXin Qiu, David Rassin, Marjorie Grafe, Tom Wood & J. Regino Perez-Polo

Authors
  1. Joel N. Glasgow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JingXin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Rassin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marjorie Grafe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tom Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Regino Perez-Polo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glasgow, J.N., Qiu, J., Rassin, D. et al. Transcriptional Regulation of the BCL-X Gene by NF-κB Is an Element of Hypoxic Responses in the Rat Brain. Neurochem Res 26, 647–659 (2001). https://doi.org/10.1023/A:1010987220034

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1010987220034

Search

Navigation