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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1999 Sep 29;354(1389):1601–1609. doi: 10.1098/rstb.1999.0504

Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha.

R T Hay 1, L Vuillard 1, J M Desterro 1, M S Rodriguez 1
PMCID: PMC1692667  PMID: 10582246

Abstract

In unstimulated cells the transcription factor NF-kappa B is held in the cytoplasm in an inactive state by I kappa B inhibitor proteins. Ultimately activation of NF-kappa B is achieved by ubiquitination and proteasome-mediated degradation of I kappa B alpha and we have therefore investigated factors which control this proteolysis. Signal-induced degradation of I kappa B alpha exposes the nuclear localization signal of NF-kappa B, thus allowing it to translocate into the nucleus and activate transcription from responsive genes. An autoregulatory loop is established when NF-kappa B induces expression of the I kappa B alpha gene and newly synthesized I kappa B alpha accumulates in the nucleus where it negatively regulates NF-kappa B-dependent transcription. As part of this post-induction repression, the nuclear export signal on I kappa B alpha mediates transport of NF-kappa B-I kappa B alpha complexes from the nucleus to the cytoplasm. As nuclear export of I kappa B alpha is blocked by leptomycin B this drug was used to examine the effect of cellular location on susceptibility of I kappa B alpha to signal-induced degradation. In the presence of leptomycin B, I kappa B alpha is accumulated in the nucleus and in this compartment is resistant to signal-induced degradation. Thus signal-induced degradation of I kappa B alpha is mainly, if not exclusively a cytoplasmic process. An efficient nuclear export of I kappa B alpha is therefore essential for maintaining a low level of I kappa B alpha in the nucleus and allowing NF-kappa B to be transcriptionally active upon cell stimulation. We have detected a modified form of I kappa B alpha, conjugated to the small ubiquitin-like protein SUMO-1, which is resistant to signal-induced degradation. SUMO-1 modified I kappa B alpha remains associated with NF-kappa B and thus overexpression of SUMO-1 inhibits the signal-induced activation of NF-kappa B-dependent transcription. Reconstitution of the conjugation reaction with highly purified proteins demonstrated that in the presence of a novel E1 SUMO-1 activating enzyme, Ubch9 directly conjugated SUMO-1 to I kappa B alpha on residues K21 and K22, which are also used for ubiquitin modification. Thus, while ubiquitination targets proteins for rapid degradation, SUMO-1 modification acts antagonistically to generate proteins resistant to degradation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arenzana-Seisdedos F., Thompson J., Rodriguez M. S., Bachelerie F., Thomas D., Hay R. T. Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B. Mol Cell Biol. 1995 May;15(5):2689–2696. doi: 10.1128/mcb.15.5.2689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arenzana-Seisdedos F., Turpin P., Rodriguez M., Thomas D., Hay R. T., Virelizier J. L., Dargemont C. Nuclear localization of I kappa B alpha promotes active transport of NF-kappa B from the nucleus to the cytoplasm. J Cell Sci. 1997 Feb;110(Pt 3):369–378. doi: 10.1242/jcs.110.3.369. [DOI] [PubMed] [Google Scholar]
  3. Baldi L., Brown K., Franzoso G., Siebenlist U. Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of I kappa B-alpha. J Biol Chem. 1996 Jan 5;271(1):376–379. doi: 10.1074/jbc.271.1.376. [DOI] [PubMed] [Google Scholar]
  4. Beg A. A., Finco T. S., Nantermet P. V., Baldwin A. S., Jr 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. 1993 Jun;13(6):3301–3310. doi: 10.1128/mcb.13.6.3301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beg A. A., Sha W. C., Bronson R. T., Baltimore D. Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev. 1995 Nov 15;9(22):2736–2746. doi: 10.1101/gad.9.22.2736. [DOI] [PubMed] [Google Scholar]
  6. Blank V., Kourilsky P., Israël A. Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus. EMBO J. 1991 Dec;10(13):4159–4167. doi: 10.1002/j.1460-2075.1991.tb04994.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boddy M. N., Howe K., Etkin L. D., Solomon E., Freemont P. S. PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene. 1996 Sep 5;13(5):971–982. [PubMed] [Google Scholar]
  8. Bours V., Burd P. R., Brown K., Villalobos J., Park S., Ryseck R. P., Bravo R., Kelly K., Siebenlist U. A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site. Mol Cell Biol. 1992 Feb;12(2):685–695. doi: 10.1128/mcb.12.2.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brockman J. A., Scherer D. C., McKinsey T. A., Hall S. M., Qi X., Lee W. Y., Ballard D. W. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol. 1995 May;15(5):2809–2818. doi: 10.1128/mcb.15.5.2809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brown K., Gerstberger S., Carlson L., Franzoso G., Siebenlist U. Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995 Mar 10;267(5203):1485–1488. doi: 10.1126/science.7878466. [DOI] [PubMed] [Google Scholar]
  11. Chen Z. J., Parent L., Maniatis T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell. 1996 Mar 22;84(6):853–862. doi: 10.1016/s0092-8674(00)81064-8. [DOI] [PubMed] [Google Scholar]
  12. Chen Z., Hagler J., Palombella V. J., Melandri F., Scherer D., Ballard D., Maniatis T. Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev. 1995 Jul 1;9(13):1586–1597. doi: 10.1101/gad.9.13.1586. [DOI] [PubMed] [Google Scholar]
  13. Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. doi: 10.1016/0092-8674(94)90396-4. [DOI] [PubMed] [Google Scholar]
  14. Cohen L., Henzel W. J., Baeuerle P. A. IKAP is a scaffold protein of the IkappaB kinase complex. Nature. 1998 Sep 17;395(6699):292–296. doi: 10.1038/26254. [DOI] [PubMed] [Google Scholar]
  15. Cressman D. E., Taub R. I kappa B alpha can localize in the nucleus but shows no direct transactivation potential. Oncogene. 1993 Sep;8(9):2567–2573. [PubMed] [Google Scholar]
  16. Desterro J. M., Rodriguez M. S., Hay R. T. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Mol Cell. 1998 Aug;2(2):233–239. doi: 10.1016/s1097-2765(00)80133-1. [DOI] [PubMed] [Google Scholar]
  17. Desterro J. M., Thomson J., Hay R. T. Ubch9 conjugates SUMO but not ubiquitin. FEBS Lett. 1997 Nov 17;417(3):297–300. doi: 10.1016/s0014-5793(97)01305-7. [DOI] [PubMed] [Google Scholar]
  18. DiDonato J. A., Hayakawa M., Rothwarf D. M., Zandi E., Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997 Aug 7;388(6642):548–554. doi: 10.1038/41493. [DOI] [PubMed] [Google Scholar]
  19. DiDonato J., Mercurio F., Rosette C., Wu-Li J., Suyang H., Ghosh S., Karin M. Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol. 1996 Apr;16(4):1295–1304. doi: 10.1128/mcb.16.4.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dohmen R. J., Stappen R., McGrath J. P., Forrová H., Kolarov J., Goffeau A., Varshavsky A. An essential yeast gene encoding a homolog of ubiquitin-activating enzyme. J Biol Chem. 1995 Jul 28;270(30):18099–18109. doi: 10.1074/jbc.270.30.18099. [DOI] [PubMed] [Google Scholar]
  21. Duprez E., Saurin A. J., Desterro J. M., Lallemand-Breitenbach V., Howe K., Boddy M. N., Solomon E., de Thé H., Hay R. T., Freemont P. S. SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. J Cell Sci. 1999 Feb;112(Pt 3):381–393. doi: 10.1242/jcs.112.3.381. [DOI] [PubMed] [Google Scholar]
  22. Fischer U., Huber J., Boelens W. C., Mattaj I. W., Lührmann R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell. 1995 Aug 11;82(3):475–483. doi: 10.1016/0092-8674(95)90436-0. [DOI] [PubMed] [Google Scholar]
  23. Fornerod M., Ohno M., Yoshida M., Mattaj I. W. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997 Sep 19;90(6):1051–1060. doi: 10.1016/s0092-8674(00)80371-2. [DOI] [PubMed] [Google Scholar]
  24. Fornerod M., van Deursen J., van Baal S., Reynolds A., Davis D., Murti K. G., Fransen J., Grosveld G. The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J. 1997 Feb 17;16(4):807–816. doi: 10.1093/emboj/16.4.807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fritz C. C., Green M. R. HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs. Curr Biol. 1996 Jul 1;6(7):848–854. doi: 10.1016/s0960-9822(02)00608-5. [DOI] [PubMed] [Google Scholar]
  26. Fukuda M., Asano S., Nakamura T., Adachi M., Yoshida M., Yanagida M., Nishida E. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997 Nov 20;390(6657):308–311. doi: 10.1038/36894. [DOI] [PubMed] [Google Scholar]
  27. Ghosh S., Gifford A. M., Riviere L. R., Tempst P., Nolan G. P., Baltimore D. Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019–1029. doi: 10.1016/0092-8674(90)90276-k. [DOI] [PubMed] [Google Scholar]
  28. Handley P. M., Mueckler M., Siegel N. R., Ciechanover A., Schwartz A. L. Molecular cloning, sequence, and tissue distribution of the human ubiquitin-activating enzyme E1. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):258–262. doi: 10.1073/pnas.88.1.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Haskill S., Beg A. A., Tompkins S. M., Morris J. S., Yurochko A. D., Sampson-Johannes A., Mondal K., Ralph P., Baldwin A. S., Jr Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell. 1991 Jun 28;65(7):1281–1289. doi: 10.1016/0092-8674(91)90022-q. [DOI] [PubMed] [Google Scholar]
  30. Henkel T., Machleidt T., Alkalay I., Krönke M., Ben-Neriah Y., Baeuerle P. A. Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature. 1993 Sep 9;365(6442):182–185. doi: 10.1038/365182a0. [DOI] [PubMed] [Google Scholar]
  31. Hershko A., Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479. doi: 10.1146/annurev.biochem.67.1.425. [DOI] [PubMed] [Google Scholar]
  32. Inoue J., Kerr L. D., Kakizuka A., Verma I. M. 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. 1992 Mar 20;68(6):1109–1120. doi: 10.1016/0092-8674(92)90082-n. [DOI] [PubMed] [Google Scholar]
  33. Jaffray E., Wood K. M., Hay R. T. Domain organization of I kappa B alpha and sites of interaction with NF-kappa B p65. Mol Cell Biol. 1995 Apr;15(4):2166–2172. doi: 10.1128/mcb.15.4.2166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Johnson E. S., Blobel G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J Biol Chem. 1997 Oct 24;272(43):26799–26802. doi: 10.1074/jbc.272.43.26799. [DOI] [PubMed] [Google Scholar]
  35. Johnson E. S., Ma P. C., Ota I. M., Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem. 1995 Jul 21;270(29):17442–17456. doi: 10.1074/jbc.270.29.17442. [DOI] [PubMed] [Google Scholar]
  36. Johnson E. S., Schwienhorst I., Dohmen R. J., Blobel G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. EMBO J. 1997 Sep 15;16(18):5509–5519. doi: 10.1093/emboj/16.18.5509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Karin M., Delhase M. JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9067–9069. doi: 10.1073/pnas.95.16.9067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kieran M., Blank V., Logeat F., Vandekerckhove J., Lottspeich F., Le Bail O., Urban M. B., Kourilsky P., Baeuerle P. A., Israël A. The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell. 1990 Sep 7;62(5):1007–1018. doi: 10.1016/0092-8674(90)90275-j. [DOI] [PubMed] [Google Scholar]
  39. King R. W., Glotzer M., Kirschner M. W. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol Biol Cell. 1996 Sep;7(9):1343–1357. doi: 10.1091/mbc.7.9.1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Kroll M., Conconi M., Desterro M. J., Marin A., Thomas D., Friguet B., Hay R. T., Virelizier J. L., Arenzana-Seisdedos F., Rodriguez M. S. The carboxy-terminus of I kappaB alpha determines susceptibility to degradation by the catalytic core of the proteasome. Oncogene. 1997 Oct 9;15(15):1841–1850. doi: 10.1038/sj.onc.1201560. [DOI] [PubMed] [Google Scholar]
  41. Lammer D., Mathias N., Laplaza J. M., Jiang W., Liu Y., Callis J., Goebl M., Estelle M. Modification of yeast Cdc53p by the ubiquitin-related protein rub1p affects function of the SCFCdc4 complex. Genes Dev. 1998 Apr 1;12(7):914–926. doi: 10.1101/gad.12.7.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Li C. C., Dai R. M., Longo D. L. Inactivation of NF-kappa B inhibitor I kappa B alpha: ubiquitin-dependent proteolysis and its degradation product. Biochem Biophys Res Commun. 1995 Oct 4;215(1):292–301. doi: 10.1006/bbrc.1995.2465. [DOI] [PubMed] [Google Scholar]
  43. Liakopoulos D., Doenges G., Matuschewski K., Jentsch S. A novel protein modification pathway related to the ubiquitin system. EMBO J. 1998 Apr 15;17(8):2208–2214. doi: 10.1093/emboj/17.8.2208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Liou H. C., Nolan G. P., Ghosh S., Fujita T., Baltimore D. The NF-kappa B p50 precursor, p105, contains an internal I kappa B-like inhibitor that preferentially inhibits p50. EMBO J. 1992 Aug;11(8):3003–3009. doi: 10.1002/j.1460-2075.1992.tb05370.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Mahajan R., Delphin C., Guan T., Gerace L., Melchior F. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997 Jan 10;88(1):97–107. doi: 10.1016/s0092-8674(00)81862-0. [DOI] [PubMed] [Google Scholar]
  46. Mahajan R., Gerace L., Melchior F. Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. J Cell Biol. 1998 Jan 26;140(2):259–270. doi: 10.1083/jcb.140.2.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Malinin N. L., Boldin M. P., Kovalenko A. V., Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature. 1997 Feb 6;385(6616):540–544. doi: 10.1038/385540a0. [DOI] [PubMed] [Google Scholar]
  48. Matunis M. J., Coutavas E., Blobel G. A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol. 1996 Dec;135(6 Pt 1):1457–1470. doi: 10.1083/jcb.135.6.1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Matunis M. J., Wu J., Blobel G. SUMO-1 modification and its role in targeting the Ran GTPase-activating protein, RanGAP1, to the nuclear pore complex. J Cell Biol. 1998 Feb 9;140(3):499–509. doi: 10.1083/jcb.140.3.499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Mellits K. H., Hay R. T., Goodbourn S. 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. 1993 Nov 11;21(22):5059–5066. doi: 10.1093/nar/21.22.5059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Mercurio F., DiDonato J. A., Rosette C., Karin M. p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev. 1993 Apr;7(4):705–718. doi: 10.1101/gad.7.4.705. [DOI] [PubMed] [Google Scholar]
  52. Mercurio F., Didonato J., Rosette C., Karin M. Molecular cloning and characterization of a novel Rel/NF-kappa B family member displaying structural and functional homology to NF-kappa B p50/p105. DNA Cell Biol. 1992 Sep;11(7):523–537. doi: 10.1089/dna.1992.11.523. [DOI] [PubMed] [Google Scholar]
  53. Mercurio F., Zhu H., Murray B. W., Shevchenko A., Bennett B. L., Li J., Young D. B., Barbosa M., Mann M., Manning A. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science. 1997 Oct 31;278(5339):860–866. doi: 10.1126/science.278.5339.860. [DOI] [PubMed] [Google Scholar]
  54. Müller S., Matunis M. J., Dejean A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 1998 Jan 2;17(1):61–70. doi: 10.1093/emboj/17.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Neri A., Chang C. C., Lombardi L., Salina M., Corradini P., Maiolo A. T., Chaganti R. S., Dalla-Favera R. B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell. 1991 Dec 20;67(6):1075–1087. doi: 10.1016/0092-8674(91)90285-7. [DOI] [PubMed] [Google Scholar]
  56. Nolan G. P., Ghosh S., Liou H. C., Tempst P., Baltimore D. DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell. 1991 Mar 8;64(5):961–969. doi: 10.1016/0092-8674(91)90320-x. [DOI] [PubMed] [Google Scholar]
  57. Ohno H., Takimoto G., McKeithan T. W. The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control. Cell. 1990 Mar 23;60(6):991–997. doi: 10.1016/0092-8674(90)90347-h. [DOI] [PubMed] [Google Scholar]
  58. Ossareh-Nazari B., Bachelerie F., Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997 Oct 3;278(5335):141–144. doi: 10.1126/science.278.5335.141. [DOI] [PubMed] [Google Scholar]
  59. Palmer A., Rivett A. J., Thomson S., Hendil K. B., Butcher G. W., Fuertes G., Knecht E. Subpopulations of proteasomes in rat liver nuclei, microsomes and cytosol. Biochem J. 1996 Jun 1;316(Pt 2):401–407. doi: 10.1042/bj3160401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Rodriguez M. S., Michalopoulos I., Arenzana-Seisdedos F., Hay R. T. Inducible degradation of I kappa B alpha in vitro and in vivo requires the acidic C-terminal domain of the protein. Mol Cell Biol. 1995 May;15(5):2413–2419. doi: 10.1128/mcb.15.5.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Rodriguez M. S., Thompson J., Hay R. T., Dargemont C. Nuclear retention of IkappaBalpha protects it from signal-induced degradation and inhibits nuclear factor kappaB transcriptional activation. J Biol Chem. 1999 Mar 26;274(13):9108–9115. doi: 10.1074/jbc.274.13.9108. [DOI] [PubMed] [Google Scholar]
  62. Rodriguez M. S., Wright J., Thompson J., Thomas D., Baleux F., Virelizier J. L., Hay R. T., Arenzana-Seisdedos F. Identification of lysine residues required for signal-induced ubiquitination and degradation of I kappa B-alpha in vivo. Oncogene. 1996 Jun 6;12(11):2425–2435. [PubMed] [Google Scholar]
  63. Roff M., Thompson J., Rodriguez M. S., Jacque J. M., Baleux F., Arenzana-Seisdedos F., Hay R. T. Role of IkappaBalpha ubiquitination in signal-induced activation of NFkappaB in vivo. J Biol Chem. 1996 Mar 29;271(13):7844–7850. doi: 10.1074/jbc.271.13.7844. [DOI] [PubMed] [Google Scholar]
  64. Rogove A. D., Tsirka S. E. Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Curr Biol. 1998 Jan 1;8(1):19–25. doi: 10.1016/s0960-9822(98)70016-8. [DOI] [PubMed] [Google Scholar]
  65. Roth J., Dobbelstein M., Freedman D. A., Shenk T., Levine A. J. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. EMBO J. 1998 Jan 15;17(2):554–564. doi: 10.1093/emboj/17.2.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Rothwarf D. M., Zandi E., Natoli G., Karin M. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature. 1998 Sep 17;395(6699):297–300. doi: 10.1038/26261. [DOI] [PubMed] [Google Scholar]
  67. Ruben S. M., Dillon P. J., Schreck R., Henkel T., Chen C. H., Maher M., Baeuerle P. A., Rosen C. A. Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science. 1991 Mar 22;251(5000):1490–1493. doi: 10.1126/science.2006423. [DOI] [PubMed] [Google Scholar]
  68. Ryseck R. P., Bull P., Takamiya M., Bours V., Siebenlist U., Dobrzanski P., Bravo R. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol Cell Biol. 1992 Feb;12(2):674–684. doi: 10.1128/mcb.12.2.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Régnier C. H., Song H. Y., Gao X., Goeddel D. V., Cao Z., Rothe M. Identification and characterization of an IkappaB kinase. Cell. 1997 Jul 25;90(2):373–383. doi: 10.1016/s0092-8674(00)80344-x. [DOI] [PubMed] [Google Scholar]
  70. Sachdev S., Hoffmann A., Hannink M. Nuclear localization of IkappaB alpha is mediated by the second ankyrin repeat: the IkappaB alpha ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol Cell Biol. 1998 May;18(5):2524–2534. doi: 10.1128/mcb.18.5.2524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Saitoh H., Pu R., Cavenagh M., Dasso M. RanBP2 associates with Ubc9p and a modified form of RanGAP1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3736–3741. doi: 10.1073/pnas.94.8.3736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Saitoh H., Sparrow D. B., Shiomi T., Pu R. T., Nishimoto T., Mohun T. J., Dasso M. Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2. Curr Biol. 1998 Jan 15;8(2):121–124. doi: 10.1016/s0960-9822(98)70044-2. [DOI] [PubMed] [Google Scholar]
  73. Scherer D. C., Brockman J. A., Chen Z., Maniatis T., Ballard D. W. Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11259–11263. doi: 10.1073/pnas.92.24.11259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Schmid R. M., Perkins N. D., Duckett C. S., Andrews P. C., Nabel G. J. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. doi: 10.1038/352733a0. [DOI] [PubMed] [Google Scholar]
  75. Schwarz S. E., Matuschewski K., Liakopoulos D., Scheffner M., Jentsch S. The ubiquitin-like proteins SMT3 and SUMO-1 are conjugated by the UBC9 E2 enzyme. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):560–564. doi: 10.1073/pnas.95.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Seufert W., Futcher B., Jentsch S. Role of a ubiquitin-conjugating enzyme in degradation of S- and M-phase cyclins. Nature. 1995 Jan 5;373(6509):78–81. doi: 10.1038/373078a0. [DOI] [PubMed] [Google Scholar]
  77. Shen Z., Pardington-Purtymun P. E., Comeaux J. C., Moyzis R. K., Chen D. J. UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics. 1996 Sep 1;36(2):271–279. doi: 10.1006/geno.1996.0462. [DOI] [PubMed] [Google Scholar]
  78. Stade K., Ford C. S., Guthrie C., Weis K. Exportin 1 (Crm1p) is an essential nuclear export factor. Cell. 1997 Sep 19;90(6):1041–1050. doi: 10.1016/s0092-8674(00)80370-0. [DOI] [PubMed] [Google Scholar]
  79. Sternsdorf T., Jensen K., Will H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J Cell Biol. 1997 Dec 29;139(7):1621–1634. doi: 10.1083/jcb.139.7.1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Sun S., Elwood J., Greene W. C. Both amino- and carboxyl-terminal sequences within I kappa B alpha regulate its inducible degradation. Mol Cell Biol. 1996 Mar;16(3):1058–1065. doi: 10.1128/mcb.16.3.1058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Thompson J. E., Phillips R. J., Erdjument-Bromage H., Tempst P., Ghosh S. I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell. 1995 Feb 24;80(4):573–582. doi: 10.1016/0092-8674(95)90511-1. [DOI] [PubMed] [Google Scholar]
  82. Traenckner E. B., Pahl H. L., Henkel T., Schmidt K. N., Wilk S., Baeuerle P. A. 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. 1995 Jun 15;14(12):2876–2883. doi: 10.1002/j.1460-2075.1995.tb07287.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Turpin P., Hay R. T., Dargemont C. Characterization of IkappaBalpha nuclear import pathway. J Biol Chem. 1999 Mar 5;274(10):6804–6812. doi: 10.1074/jbc.274.10.6804. [DOI] [PubMed] [Google Scholar]
  84. Verma I. M., Stevenson J. K., Schwarz E. M., Van Antwerp D., Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995 Nov 15;9(22):2723–2735. doi: 10.1101/gad.9.22.2723. [DOI] [PubMed] [Google Scholar]
  85. Wen W., Meinkoth J. L., Tsien R. Y., Taylor S. S. Identification of a signal for rapid export of proteins from the nucleus. Cell. 1995 Aug 11;82(3):463–473. doi: 10.1016/0092-8674(95)90435-2. [DOI] [PubMed] [Google Scholar]
  86. Whiteside S. T., Epinat J. C., Rice N. R., Israël A. I kappa B epsilon, a novel member of the I kappa B family, controls RelA and cRel NF-kappa B activity. EMBO J. 1997 Mar 17;16(6):1413–1426. doi: 10.1093/emboj/16.6.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Whiteside S. T., Ernst M. K., LeBail O., Laurent-Winter C., Rice N., Israël A. 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. 1995 Oct;15(10):5339–5345. doi: 10.1128/mcb.15.10.5339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Wilhelmsen K. C., Eggleton K., Temin H. M. Nucleic acid sequences of the oncogene v-rel in reticuloendotheliosis virus strain T and its cellular homolog, the proto-oncogene c-rel. J Virol. 1984 Oct;52(1):172–182. doi: 10.1128/jvi.52.1.172-182.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Wolff B., Sanglier J. J., Wang Y. Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol. 1997 Feb;4(2):139–147. doi: 10.1016/s1074-5521(97)90257-x. [DOI] [PubMed] [Google Scholar]
  90. Woronicz J. D., Gao X., Cao Z., Rothe M., Goeddel D. V. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997 Oct 31;278(5339):866–869. doi: 10.1126/science.278.5339.866. [DOI] [PubMed] [Google Scholar]
  91. Wójcik C., Paweletz N., Schroeter D. Localization of proteasomal antigens during different phases of the cell cycle in HeLa cells. Eur J Cell Biol. 1995 Oct;68(2):191–198. [PubMed] [Google Scholar]
  92. Yamaoka S., Courtois G., Bessia C., Whiteside S. T., Weil R., Agou F., Kirk H. E., Kay R. J., Israël A. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell. 1998 Jun 26;93(7):1231–1240. doi: 10.1016/s0092-8674(00)81466-x. [DOI] [PubMed] [Google Scholar]
  93. Yaron A., Gonen H., Alkalay I., Hatzubai A., Jung S., Beyth S., Mercurio F., Manning A. M., Ciechanover A., Ben-Neriah Y. Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase. EMBO J. 1997 Nov 3;16(21):6486–6494. doi: 10.1093/emboj/16.21.6486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Zabel U., Henkel T., Silva M. S., Baeuerle P. A. Nuclear uptake control of NF-kappa B by MAD-3, an I kappa B protein present in the nucleus. EMBO J. 1993 Jan;12(1):201–211. doi: 10.1002/j.1460-2075.1993.tb05646.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Zandi E., Rothwarf D. M., Delhase M., Hayakawa M., Karin M. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell. 1997 Oct 17;91(2):243–252. doi: 10.1016/s0092-8674(00)80406-7. [DOI] [PubMed] [Google Scholar]

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