Molecular and Cellular Biochemistry

, Volume 328, Issue 1–2, pp 9–16 | Cite as

Old target new approach: an alternate NF-κB activation pathway via translation inhibition

  • Csaba F. László
  • Shiyong Wu


Activation of the transcription factor NF-κB is a highly regulated multi-level process. The critical step during activation is the release from its inhibitor IκB, which as any other protein is under the direct influence of translation regulation. In this review, we summarize in detail the current understanding of the impact of translational regulation on NF-κB activation. We illustrate a newly developed mechanism of eIF2α kinase-mediated IκB depletion and subsequent NF-κB activation. We also show that the classical NF-κB activation pathways occur simultaneously with, and are complemented by, translational down regulation of the inhibitor molecule IκB, the importance of one or the other being shifted in accordance with the type and magnitude of the stressing agent or stimuli.


Inhibitor of nuclear factor κB Nuclear factor κB Eukaryotic initiation factor 2 eIF2α kinase IκB kinase 



This work was supported by National Institutes of Health Grant RO1 CA86926 (to S. W.) and R56 CA086928 (to S. W.).


  1. 1.
    Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716. doi: 10.1016/0092-8674(86)90346-6 PubMedGoogle Scholar
  2. 2.
    Sen R, Baltimore D (1986) Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47:921–928. doi: 10.1016/0092-8674(86)90807-X PubMedGoogle Scholar
  3. 3.
    Baldwin AS Jr (2001) Series introduction: the transcription factor NF-kappaB and human disease. J Clin Investig 107:3–6. doi: 10.1172/JCI11891 PubMedGoogle Scholar
  4. 4.
    Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3:221–227. doi: 10.1038/ni0302-221 PubMedGoogle Scholar
  5. 5.
    Duckett CS, Perkins ND, Kowalik TF et al (1993) Dimerization of NF-KB2 with RelA(p65) regulates DNA binding, transcriptional activation, and inhibition by an I kappa B-alpha (MAD-3). Mol Cell Biol 13:1315–1322PubMedGoogle Scholar
  6. 6.
    Grimm S, Baeuerle PA (1993) The inducible transcription factor NF-kappa B: structure–function relationship of its protein subunits. Biochem J 290(Pt 2):297–308PubMedGoogle Scholar
  7. 7.
    Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18:2195–2224. doi: 10.1101/gad.1228704 PubMedGoogle Scholar
  8. 8.
    Caamano J, Hunter CA (2002) NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev 15:414–429. doi: 10.1128/CMR.15.3.414-429.2002 PubMedGoogle Scholar
  9. 9.
    Zhong H, May MJ, Jimi E et al (2002) The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol Cell 9:625–636. doi: 10.1016/S1097-2765(02)00477-X PubMedGoogle Scholar
  10. 10.
    Baeuerle PA, Baltimore D (1988) Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell 53:211–217. doi: 10.1016/0092-8674(88)90382-0 PubMedGoogle Scholar
  11. 11.
    Baeuerle PA, Baltimore D (1988) I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242:540–546. doi: 10.1126/science.3140380 PubMedGoogle Scholar
  12. 12.
    Naumann M, Nieters A, Hatada EN et al (1993) NF-kappa B precursor p100 inhibits nuclear translocation and DNA binding of NF-kappa B/rel-factors. Oncogene 8:2275–2281PubMedGoogle Scholar
  13. 13.
    Naumann M, Wulczyn FG, Scheidereit C (1993) The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B. EMBO J 12:213–222PubMedGoogle Scholar
  14. 14.
    Huxford T, Huang DB, Malek S et al (1998) The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell 95:759–770. doi: 10.1016/S0092-8674(00)81699-2 PubMedGoogle Scholar
  15. 15.
    Malek S, Huxford T, Ghosh G (1998) Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB. J Biol Chem 273:25427–25435. doi: 10.1074/jbc.273.39.25427 PubMedGoogle Scholar
  16. 16.
    Jacobs MD, Harrison SC (1998) Structure of an IkappaBalpha/NF-kappaB complex. Cell 95:749–758. doi: 10.1016/S0092-8674(00)81698-0 PubMedGoogle Scholar
  17. 17.
    Naumann M, Scheidereit C (1994) Activation of NF-kappa B in vivo is regulated by multiple phosphorylations. EMBO J 13:4597–4607PubMedGoogle Scholar
  18. 18.
    Zhong H, Voll RE, Ghosh S (1998) Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell 1:661–671. doi: 10.1016/S1097-2765(00)80066-0 PubMedGoogle Scholar
  19. 19.
    Okazaki T, Sakon S, Sasazuki T et al (2003) Phosphorylation of serine 276 is essential for p65 NF-kappaB subunit-dependent cellular responses. Biochem Biophys Res Commun 300:807–812. doi: 10.1016/S0006-291X(02)02932-7 PubMedGoogle Scholar
  20. 20.
    Wang D, Baldwin AS Jr (1998) Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J Biol Chem 273:29411–29416. doi: 10.1074/jbc.273.45.29411 PubMedGoogle Scholar
  21. 21.
    Wang D, Westerheide SD, Hanson JL et al (2000) Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 275:32592–32597. doi: 10.1074/jbc.M001358200 PubMedGoogle Scholar
  22. 22.
    Sakurai H, Chiba H, Miyoshi H et al (1999) IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274:30353–30356. doi: 10.1074/jbc.274.43.30353 PubMedGoogle Scholar
  23. 23.
    Tergaonkar V, Bottero V, Ikawa M et al (2003) IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol 23:8070–8083. doi: 10.1128/MCB.23.22.8070-8083.2003 PubMedGoogle Scholar
  24. 24.
    Arenzana-Seisdedos F, Thompson J, Rodriguez MS et al (1995) Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol 15:2689–2696PubMedGoogle Scholar
  25. 25.
    Brown K, Park S, Kanno T et al (1993) Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. Proc Natl Acad Sci USA 90:2532–2536. doi: 10.1073/pnas.90.6.2532 PubMedGoogle Scholar
  26. 26.
    Malek S, Chen Y, Huxford T et al (2001) IkappaBbeta, but not IkappaBalpha, functions as a classical cytoplasmic inhibitor of NF-kappaB dimers by masking both NF-kappaB nuclear localization sequences in resting cells. J Biol Chem 276:45225–45235. doi: 10.1074/jbc.M105865200 PubMedGoogle Scholar
  27. 27.
    Malek S, Huang DB, Huxford T et al (2003) X-ray crystal structure of an IkappaBbeta × NF-kappaB p65 homodimer complex. J Biol Chem 278:23094–23100. doi: 10.1074/jbc.M301022200 PubMedGoogle Scholar
  28. 28.
    Huang TT, Feinberg SL, Suryanarayanan S et al (2002) The zinc finger domain of NEMO is selectively required for NF-kappa B activation by UV radiation and topoisomerase inhibitors. Mol Cell Biol 22:5813–5825. doi: 10.1128/MCB.22.16.5813-5825.2002 PubMedGoogle Scholar
  29. 29.
    Rothwarf DM, Zandi E, Natoli G et al (1998) IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395:297–300. doi: 10.1038/26261 PubMedGoogle Scholar
  30. 30.
    Zandi E, Rothwarf DM, Delhase M et al (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91:243–252. doi: 10.1016/S0092-8674(00)80406-7 PubMedGoogle Scholar
  31. 31.
    Karin M (1999) The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem 274:27339–27342. doi: 10.1074/jbc.274.39.27339 PubMedGoogle Scholar
  32. 32.
    Laszlo CF, Wu S (2008) Mechanism of UV-induced IkappaBalpha-independent activation of NF-kappaB. Photochem Photobiol 84:1564–1568PubMedGoogle Scholar
  33. 33.
    Wu S, Tan M, Hu Y et al (2004) Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J Biol Chem 279:34898–34902. doi: 10.1074/jbc.M405616200 PubMedGoogle Scholar
  34. 34.
    Koumenis C, Naczki C, Koritzinsky M et al (2002) Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 22:7405–7416. doi: 10.1128/MCB.22.21.7405-7416.2002 PubMedGoogle Scholar
  35. 35.
    Curry HA, Clemens RA, Shah S et al (1999) Heat shock inhibits radiation-induced activation of NF-kappaB via inhibition of I-kappaB kinase. J Biol Chem 274:23061–23067. doi: 10.1074/jbc.274.33.23061 PubMedGoogle Scholar
  36. 36.
    Hershey JW, Asano K, Naranda T et al (1996) Conservation and diversity in the structure of translation initiation factor EIF3 from humans and yeast. Biochimie 78:903–907. doi: 10.1016/S0300-9084(97)86711-9 PubMedGoogle Scholar
  37. 37.
    Pain VM (1996) Initiation of protein synthesis in eukaryotic cells. Eur J Biochem 236:747–771. doi: 10.1111/j.1432-1033.1996.00747.x PubMedGoogle Scholar
  38. 38.
    Sudhakar A, Ramachandran A, Ghosh S et al (2000) Phosphorylation of serine 51 in initiation factor 2 alpha (eIF2 alpha) promotes complex formation between eIF2 alpha(P) and eIF2B and causes inhibition in the guanine nucleotide exchange activity of eIF2B. Biochemistry 39:12929–12938. doi: 10.1021/bi0008682 PubMedGoogle Scholar
  39. 39.
    Deng J, Lu PD, Zhang Y et al (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24:10161–10168. doi: 10.1128/MCB.24.23.10161-10168.2004 PubMedGoogle Scholar
  40. 40.
    Wek RC (1994) eIF-2 kinases: regulators of general and gene-specific translation initiation. Trends Biochem Sci 19:491–496. doi: 10.1016/0968-0004(94)90136-8 PubMedGoogle Scholar
  41. 41.
    Chen JJ, London IM (1995) Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Trends Biochem Sci 20:105–108. doi: 10.1016/S0968-0004(00)88975-6 PubMedGoogle Scholar
  42. 42.
    Chefalo PJ, Oh J, Rafie-Kolpin M et al (1998) Heme-regulated eIF-2alpha kinase purifies as a hemoprotein. Eur J Biochem 258:820–830. doi: 10.1046/j.1432-1327.1998.2580820.x PubMedGoogle Scholar
  43. 43.
    Maxwell CR, Rabinovitz M (1969) Evidence for an inhibitor in the control of globin synthesis by hemin in a reticulocyte lysate. Biochem Biophys Res Commun 35:79–85. doi: 10.1016/0006-291X(69)90485-9 PubMedGoogle Scholar
  44. 44.
    Bauer BN, Rafie-Kolpin M, Lu L et al (2001) Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase. Biochemistry 40:11543–11551. doi: 10.1021/bi010983s PubMedGoogle Scholar
  45. 45.
    Rafie-Kolpin M, Chefalo PJ, Hussain Z et al (2000) Two heme-binding domains of heme-regulated eukaryotic initiation factor-2alpha kinase. N terminus and kinase insertion. J Biol Chem 275:5171–5178. doi: 10.1074/jbc.275.7.5171 PubMedGoogle Scholar
  46. 46.
    Rafie-Kolpin M, Han AP, Chen JJ (2003) Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI. Biochemistry 42:6536–6544. doi: 10.1021/bi034005v PubMedGoogle Scholar
  47. 47.
    Lu L, Han AP, Chen JJ (2001) Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses. Mol Cell Biol 21:7971–7980. doi: 10.1128/MCB.21.23.7971-7980.2001 PubMedGoogle Scholar
  48. 48.
    Green SR, Mathews MB (1992) Two RNA-binding motifs in the double-stranded RNA-activated protein kinase, DAI. Genes Dev 6:2478–2490. doi: 10.1101/gad.6.12b.2478 PubMedGoogle Scholar
  49. 49.
    Galabru J, Katze MG, Robert N et al (1989) The binding of double-stranded RNA and adenovirus VAI RNA to the interferon-induced protein kinase. Eur J Biochem 178:581–589. doi: 10.1111/j.1432-1033.1989.tb14485.x PubMedGoogle Scholar
  50. 50.
    Wu S, Kaufman RJ (1997) A model for the double-stranded RNA (dsRNA)-dependent dimerization and activation of the dsRNA-activated protein kinase PKR. J Biol Chem 272:1291–1296. doi: 10.1074/jbc.272.2.1291 PubMedGoogle Scholar
  51. 51.
    Wu S, Rehemtulla A, Gupta NK et al (1996) A eukaryotic translation initiation factor 2-associated 67 kDa glycoprotein partially reverses protein synthesis inhibition by activated double-stranded RNA-dependent protein kinase in intact cells. Biochemistry 35:8275–8280. doi: 10.1021/bi953028+ PubMedGoogle Scholar
  52. 52.
    Ito T, Yang M, May WS (1999) RAX, a cellular activator for double-stranded RNA-dependent protein kinase during stress signaling. J Biol Chem 274:15427–15432. doi: 10.1074/jbc.274.22.15427 PubMedGoogle Scholar
  53. 53.
    Patel RC, Sen GC (1992) Identification of the double-stranded RNA-binding domain of the human interferon-inducible protein kinase. J Biol Chem 267:7671–7676PubMedGoogle Scholar
  54. 54.
    Kumar A, Haque J, Lacoste J et al (1994) Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci USA 91:6288–6292. doi: 10.1073/pnas.91.14.6288 PubMedGoogle Scholar
  55. 55.
    Ishii T, Kwon H, Hiscott J et al (2001) Activation of the I kappa B alpha kinase (IKK) complex by double-stranded RNA-binding defective and catalytic inactive mutants of the interferon-inducible protein kinase PKR. Oncogene 20:1900–1912. doi: 10.1038/sj.onc.1204267 PubMedGoogle Scholar
  56. 56.
    Gil J, Rullas J, Garcia MA et al (2001) The catalytic activity of dsRNA-dependent protein kinase, PKR, is required for NF-kappaB activation. Oncogene 20:385–394. doi: 10.1038/sj.onc.1204109 PubMedGoogle Scholar
  57. 57.
    Bonnet MC, Weil R, Dam E et al (2000) PKR stimulates NF-kappaB irrespective of its kinase function by interacting with the IkappaB kinase complex. Mol Cell Biol 20:4532–4542. doi: 10.1128/MCB.20.13.4532-4542.2000 PubMedGoogle Scholar
  58. 58.
    Gil J, Alcami J, Esteban M (2000) Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Oncogene 19:1369–1378. doi: 10.1038/sj.onc.1203448 PubMedGoogle Scholar
  59. 59.
    Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274. doi: 10.1038/16729 PubMedGoogle Scholar
  60. 60.
    Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233. doi: 10.1101/gad.13.10.1211 PubMedGoogle Scholar
  61. 61.
    Sonenberg N, Hershey JWB, Mathews M (2000) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, p x, 1020 ppGoogle Scholar
  62. 62.
    Brostrom CO, Bocckino SB, Brostrom MA (1983) Identification of a Ca2+ requirement for protein synthesis in eukaryotic cells. J Biol Chem 258:14390–14399PubMedGoogle Scholar
  63. 63.
    Gething MJ, Sambrook J (1992) Protein folding in the cell. Nature 355:33–45. doi: 10.1038/355033a0 PubMedGoogle Scholar
  64. 64.
    Brostrom CO, Brostrom MA (1998) Regulation of translational initiation during cellular responses to stress. Prog Nucleic Acid Res Mol Biol 58:79–125. doi: 10.1016/S0079-6603(08)60034-3 PubMedGoogle Scholar
  65. 65.
    Shi Y, Vattem KM, Sood R et al (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18:7499–7509PubMedGoogle Scholar
  66. 66.
    Jiang HY, Wek SA, McGrath BC et al (2003) Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol Cell Biol 23:5651–5663. doi: 10.1128/MCB.23.16.5651-5663.2003 PubMedGoogle Scholar
  67. 67.
    Imaizumi K, Tohyama M (2004) The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes. Nippon Yakurigaku Zasshi 124:383–390. doi: 10.1254/fpj.124.383 PubMedGoogle Scholar
  68. 68.
    Wu S, Hu Y, Wang JL et al (2002) Ultraviolet light inhibits translation through activation of the unfolded protein response kinase PERK in the lumen of the endoplasmic reticulum. J Biol Chem 277:18077–18083. doi: 10.1074/jbc.M110164200 PubMedGoogle Scholar
  69. 69.
    Pahl HL, Baeuerle PA (1996) Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers. FEBS Lett 392:129–136. doi: 10.1016/0014-5793(96)00800-9 PubMedGoogle Scholar
  70. 70.
    Berlanga JJ, Santoyo J, De Haro C (1999) Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Eur J Biochem 265:754–762. doi: 10.1046/j.1432-1327.1999.00780.x PubMedGoogle Scholar
  71. 71.
    Sood R, Porter AC, Olsen D et al (2000) A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics 154:787–801PubMedGoogle Scholar
  72. 72.
    Kimball SR, Antonetti DA, Brawley RM et al (1991) Mechanism of inhibition of peptide chain initiation by amino acid deprivation in perfused rat liver. Regulation involving inhibition of eukaryotic initiation factor 2 alpha phosphatase activity. J Biol Chem 266:1969–1976PubMedGoogle Scholar
  73. 73.
    Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11. doi: 10.1042/BST0340007 PubMedGoogle Scholar
  74. 74.
    Qiu H, Garcia-Barrio MT, Hinnebusch AG (1998) Dimerization by translation initiation factor 2 kinase GCN2 is mediated by interactions in the C-terminal ribosome-binding region and the protein kinase domain. Mol Cell Biol 18:2697–2711PubMedGoogle Scholar
  75. 75.
    Ramirez M, Wek RC, Hinnebusch AG (1991) Ribosome association of GCN2 protein kinase, a translational activator of the GCN4 gene of Saccharomyces cerevisiae. Mol Cell Biol 11:3027–3036PubMedGoogle Scholar
  76. 76.
    Jiang HY, Wek RC (2005) GCN2 phosphorylation of eIF2alpha activates NF-kappaB in response to UV irradiation. Biochem J 385:371–380. doi: 10.1042/BJ20041348 PubMedGoogle Scholar
  77. 77.
    Rosenwald IB, Koifman L, Savas L et al (2008) Expression of the translation initiation factors eIF-4E and eIF-2* is frequently increased in neoplastic cells of Hodgkin lymphoma. Hum Pathol 39:910–916. doi: 10.1016/j.humpath.2007.10.021 PubMedGoogle Scholar
  78. 78.
    Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96. doi: 10.1016/S0092-8674(02)00703-1 PubMedGoogle Scholar
  79. 79.
    Mathes E, O’Dea EL, Hoffmann A et al (2008) NF-kappaB dictates the degradation pathway of IkappaBalpha. EMBO J 27:1357–1367. doi: 10.1038/emboj.2008.73 PubMedGoogle Scholar
  80. 80.
    Krappmann D, Wulczyn FG, Scheidereit C (1996) Different mechanisms control signal-induced degradation and basal turnover of the NF-kappaB inhibitor IkappaB alpha in vivo. EMBO J 15:6716–6726PubMedGoogle Scholar
  81. 81.
    Brockman JA, Scherer DC, McKinsey TA et al (1995) Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol 15:2809–2818PubMedGoogle Scholar
  82. 82.
    Whiteside ST, Ernst MK, LeBail O et al (1995) N- and C-terminal sequences control degradation of MAD3/I kappa B alpha in response to inducers of NF-kappa B activity. Mol Cell Biol 15:5339–5345PubMedGoogle Scholar
  83. 83.
    Traenckner EB, Pahl HL, Henkel T et al (1995) Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J 14:2876–2883PubMedGoogle Scholar
  84. 84.
    Benkowski LA, Ravel JM, Browning KS (1995) mRNA binding properties of wheat germ protein synthesis initiation factor 2. Biochem Biophys Res Commun 214:1033–1039. doi: 10.1006/bbrc.1995.2389 PubMedGoogle Scholar
  85. 85.
    Scherer DC, Brockman JA, Chen Z et al (1995) Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci USA 92:11259–11263. doi: 10.1073/pnas.92.24.11259 PubMedGoogle Scholar
  86. 86.
    Baldi L, Brown K, Franzoso G et al (1996) Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha. J Biol Chem 271:376–379. doi: 10.1074/jbc.271.1.376 PubMedGoogle Scholar
  87. 87.
    Rogers S, Wells R, Rechsteiner M (1986) Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234:364–368. doi: 10.1126/science.2876518 PubMedGoogle Scholar
  88. 88.
    Sun S, Elwood J, Greene WC (1996) Both amino- and carboxyl-terminal sequences within I kappa B alpha regulate its inducible degradation. Mol Cell Biol 16:1058–1065PubMedGoogle Scholar
  89. 89.
    Aoki T, Sano Y, Yamamoto T et al (1996) The ankyrin repeats but not the PEST-like sequences are required for signal-dependent degradation of IkappaBalpha. Oncogene 12:1159–1164PubMedGoogle Scholar
  90. 90.
    Barroga CF, Stevenson JK, Schwarz EM et al (1995) Constitutive phosphorylation of I kappa B alpha by casein kinase II. Proc Natl Acad Sci USA 92:7637–7641. doi: 10.1073/pnas.92.17.7637 PubMedGoogle Scholar
  91. 91.
    Mellits KH, Hay RT, Goodbourn S (1993) Proteolytic degradation of MAD3 (I kappa B alpha) and enhanced processing of the NF-kappa B precursor p105 are obligatory steps in the activation of NF-kappa B. Nucleic Acids Res 21:5059–5066. doi: 10.1093/nar/21.22.5059 PubMedGoogle Scholar
  92. 92.
    Rice NR, Ernst MK (1993) In vivo control of NF-kappa B activation by I kappa B alpha. EMBO J 12:4685–4695PubMedGoogle Scholar
  93. 93.
    Henkel T, Machleidt T, Alkalay I et al (1993) Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature 365:182–185. doi: 10.1038/365182a0 PubMedGoogle Scholar
  94. 94.
    Miyamoto S, Chiao PJ, Verma IM (1994) Enhanced I kappa B alpha degradation is responsible for constitutive NF-kappa B activity in mature murine B-cell lines. Mol Cell Biol 14:3276–3282PubMedGoogle Scholar
  95. 95.
    Pando MP, Verma IM (2000) Signal-dependent and -independent degradation of free and NF-kappa B-bound IkappaBalpha. J Biol Chem 275:21278–21286. doi: 10.1074/jbc.M002532200 PubMedGoogle Scholar
  96. 96.
    Zandi E, Chen Y, Karin M (1998) Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science 281:1360–1363. doi: 10.1126/science.281.5381.1360 PubMedGoogle Scholar
  97. 97.
    Schwarz EM, Van Antwerp D, Verma IM (1996) Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IkappaBalpha. Mol Cell Biol 16:3554–3559PubMedGoogle Scholar
  98. 98.
    Kato T Jr, Delhase M, Hoffmann A et al (2003) CK2 is a C-terminal IkappaB kinase responsible for NF-kappaB activation during the UV response. Mol Cell 12:829–839. doi: 10.1016/S1097-2765(03)00358-7 PubMedGoogle Scholar
  99. 99.
    Alvarez-Castelao B, Castano JG (2005) Mechanism of direct degradation of IkappaBalpha by 20S proteasome. FEBS Lett 579:4797–4802. doi: 10.1016/j.febslet.2005.07.060 PubMedGoogle Scholar
  100. 100.
    Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3:17–26. doi: 10.1038/nrd1279 PubMedGoogle Scholar
  101. 101.
    Jang YM, Kendaiah S, Drew B et al (2004) Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett 577:483–490. doi: 10.1016/j.febslet.2004.10.053 PubMedGoogle Scholar
  102. 102.
    Mandic A, Hansson J, Linder S et al (2003) Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem 278:9100–9106. doi: 10.1074/jbc.M210284200 PubMedGoogle Scholar
  103. 103.
    Ranganathan AC, Zhang L, Adam AP et al (2006) Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer Res 66:1702–1711. doi: 10.1158/0008-5472.CAN-05-3092 PubMedGoogle Scholar
  104. 104.
    Fribley AM, Evenchik B, Zeng Q et al (2006) Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem 281:31440–31447. doi: 10.1074/jbc.M604356200 PubMedGoogle Scholar
  105. 105.
    Meurs E, Chong K, Galabru J et al (1990) Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379–390. doi: 10.1016/0092-8674(90)90374-N PubMedGoogle Scholar
  106. 106.
    Yeung MC, Liu J, Lau AS (1996) An essential role for the interferon-inducible, double-stranded RNA-activated protein kinase PKR in the tumor necrosis factor-induced apoptosis in U937 cells. Proc Natl Acad Sci USA 93:12451–12455. doi: 10.1073/pnas.93.22.12451 PubMedGoogle Scholar
  107. 107.
    Bush KT, Goldberg AL, Nigam SK (1997) Proteasome inhibition leads to a heat-shock response, induction of endoplasmic reticulum chaperones, and thermotolerance. J Biol Chem 272:9086–9092. doi: 10.1074/jbc.272.14.9086 PubMedGoogle Scholar
  108. 108.
    Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 24:9695–9704. doi: 10.1128/MCB.24.22.9695-9704.2004 PubMedGoogle Scholar
  109. 109.
    Lee AH, Iwakoshi NN, Anderson KC et al (2003) Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 100:9946–9951. doi: 10.1073/pnas.1334037100 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of Chemistry and Biochemistry, Edison Biotechnology InstituteOhio UniversityAthensUSA

Personalised recommendations