Interaction between hnRNPA1 and IkappaBalpha is required for maximal activation of NF-kappaB-dependent transcription.
Journal: 2001/June - Molecular and Cellular Biology
ISSN: 0270-7306
Abstract:
Transcriptional activation of NF-kappaB is mediated by signal-induced phosphorylation and degradation of its inhibitor, IkappaBalpha. NF-kappaB activation induces a rapid resynthesis of IkappaBalpha which is responsible for postinduction repression of transcription. Following resynthesis, IkappaBalpha translocates to the nucleus, removes template bound NF-kappaB, and exports NF-kappaB to the cytoplasm in a transcriptionally inactive form. Here we demonstrate that IkappaBalpha interacts directly with another nucleocytoplasmic shuttling protein, hnRNPA1, both in vivo and in vitro. This interaction requires one of the N-terminal RNA binding domains of hnRNPA1 and the C-terminal region of IkappaBalpha. Cells lacking hnRNPA1 are defective in NF-kappaB-dependent transcriptional activation, but the defect in these cells is complemented by ectopic expression of hnRNPA1. hnRNPA1 expression in these cells increased the amount of IkappaBalpha degradation, compared to that of the control cells, in response to activation by Epstein-Barr virus latent membrane protein 1. Thus in addition to regulating mRNA processing and transport, hnRNPA1 also contributes to the control of NF-kappaB-dependent transcription.
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Mol Cell Biol 21(10): 3482-3490

Interaction between hnRNPA1 and IκBα Is Required for Maximal Activation of NF-κB-Dependent Transcription

Institute of Biomolecular Sciences, School of Biology, University of St. Andrews, The North Haugh, St. Andrews, KY16 9ST, Scotland, and Institut Jacques Monod, UMR 7592, 75251 Paris Cedex 05, France2
Corresponding author. Mailing address: Institute of Biomolecular Sciences, School of Biology, University of St. Andrews, The North Haugh, St. Andrews, KY16 9ST, Scotland, United Kingdom. Phone: 44 1334 463396. Fax: 44 1334 462595. E-mail: ku.ca.dna-ts@htr.
Received 2000 Oct 30; Revisions requested 2000 Nov 13; Accepted 2001 Feb 20.

Abstract

Transcriptional activation of NF-κB is mediated by signal-induced phosphorylation and degradation of its inhibitor, IκBα. NF-κB activation induces a rapid resynthesis of IκBα which is responsible for postinduction repression of transcription. Following resynthesis, IκBα translocates to the nucleus, removes template bound NF-κB, and exports NF-κB to the cytoplasm in a transcriptionally inactive form. Here we demonstrate that IκBα interacts directly with another nucleocytoplasmic shuttling protein, hnRNPA1, both in vivo and in vitro. This interaction requires one of the N-terminal RNA binding domains of hnRNPA1 and the C-terminal region of IκBα. Cells lacking hnRNPA1 are defective in NF-κB-dependent transcriptional activation, but the defect in these cells is complemented by ectopic expression of hnRNPA1. hnRNPA1 expression in these cells increased the amount of IκBα degradation, compared to that of the control cells, in response to activation by Epstein-Barr virus latent membrane protein 1. Thus in addition to regulating mRNA processing and transport, hnRNPA1 also contributes to the control of NF-κB-dependent transcription.

Abstract

The NF-κB/Rel family of transcription factors is composed of a number of structurally related, interacting proteins that bind DNA and whose activity is regulated by subcellular location. In vertebrates, this family includes p50 and p105, p52 and p100, and p65 Rel A, c-Rel, or Rel B, which bind DNA in a homo- or heterodimeric fashion and are implicated in regulation of a number of cellular genes involved in immune, inflammatory, and antiapoptotic responses (3, 5). Following cellular activation, NF-κB, typically a p50-p65 heterodimer, translocates to the nucleus and activates transcription of NF-κB-responsive genes. NF-κB dimerization, nuclear translocation, and DNA binding are facilitated by a conserved region known as the Rel homology domain. NF-κB transcriptional activity is controlled by the inhibitor IκB proteins, whose association with the NF-κB p50 and p65 subunits occludes their nuclear localization signals (NLSs), thereby leading to cytoplasmic sequestration, but also inhibits NF-κB DNA binding activity (27). Several IκBs have been described, including IκBα (25), IκBβ (63), IκBɛ (68), Bcl 3 (42), and the precursors of p50 (p105) and p52 (p100), which possess inhibitory ankyrin repeat domains that in isolation are known as IκBγ and IκBδ.

Following signal induction, IκBα is phosphorylated on serine 32 and serine 36 (8, 10, 52, 64) by the dimeric IκB kinase (16, 38, 47, 71, 75). Subsequently, IκBα is ubiquitinated on lysine 21 and lysine 22 (4, 51, 55), which targets the protein for degradation by the proteosome 26S complex. Although signal-induced modifications of IκBα are targeted to the N-terminal domain, the carboxyl-terminal domain of IκBα is also required for proteasome-mediated degradation (9, 34). Recognition of phosphorylated IκBα is accomplished by β-TrCP, which is a component of an E3 ubiquitin ligase complex which mediates ubiquitination of IκBα (26, 43, 56, 62, 67, 70, 74). After IκBα degradation, NF-κB translocates to the nucleus, where it induces the transcription of several genes, including that of its inhibitor, IκBα. Following IκBα mRNA translation, newly synthesized IκBα is accumulated in the cytoplasm and also in the nucleus, where it terminates NF-κB transcriptional activity (1). Termination of NF-κB-dependent transcription is achieved by inhibition of the NF-κB–DNA interaction and export of NF-κB back to the cytoplasm (2).

The mechanism by which IκBα localizes to the nucleus has not been precisely defined, but IκBα does not contain a region of basic residues that resembles previously characterized NLSs. However, nuclear entry of IκBα is conferred by a cis-acting nuclear import sequence located in the second ankyrin repeat which can also functionally substitute for the classical NLS in nucleoplasmin (54). Reconstitution of the nuclear import pathway in vitro indicates that IκBα is transported into the nucleus by a “piggy-back” mechanism that involves additional uncharacterized NLS-containing proteins that recognize the ankyrin repeats of IκBα (65). Nuclear export of IκBα is conferred by leucine-rich nuclear export sequences present in the carboxy-terminal (2) and amino-terminal (32) regions of the protein. The nuclear protein CRM1 (exportin 1), which belongs to the karyopherin β family (20), has been identified as the nuclear export sequence receptor (19, 21, 44, 57) and forms a complex with IκBα in the presence of GTP-bound Ran. It has been proposed that this ternary complex is transported through the nuclear pore complex and dissociates in the cytoplasm due to GTP hydrolysis by Ran, induced by Ran GTPase activating protein (19). While nuclear export of the NF-κB–IκBα complex can be demonstrated during the process of postinduction repression, pharmacological inhibition of CRM1 with leptomycin B leads to the nuclear accumulation of NF-κB and IκBα even in the uninduced state. Thus nuclear and cytoplasmic shuttling of IκBα is a highly dynamic process which, in unactivated cells, establishes a steady state where NF-κB is predominantly cytoplasmic (13, 23, 28, 32, 35, 48, 53, 61). Although the precise function of IκBα nuclear export has yet to be defined, the constant surveillance of the nucleus by IκBα results in tight and finely tuned control of NF-κB-dependent transcription.

In this study we demonstrate that IκBα interacts directly and specifically, in vitro and in vivo, with another nucleocytoplasmic shuttling protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). This interaction is mediated by the C-terminal region of IκBα and one of the N-terminal RNA binding domains of hnRNPA1. In cells lacking hnRNPA1, NF-κB activation is defective, but reintroduction of hnRNPA1 into these cells restores an efficient NF-κB response to signal induction. In the absence of hnRNPA1, IκBα does not undergo signal-induced degradation, but IκBα degradation in response to Epstein-Barr virus latent membrane protein 1 (EBV LMP-1) (60) is restored by ectopic expression of hnRNPA1. Thus in addition to regulating splicing, polyadenylation, and mRNA transport (17), hnRNPA1 also contributes to the control of NF-κB-dependent transcription.

ACKNOWLEDGMENTS

We thank Alex Houston and Ellis Jaffray, University of St. Andrews, for DNA sequencing and purified GST fusion proteins. We are grateful to Gideon Dreyfuss, University of Pennsylvania, for supplying the 4B10 monoclonal antibody to hnRNPA1 and Yaacov Ben-David, Sunnybrook Health Science Centre, Toronto, Canada, for providing the CB3 cell line.

This work was funded by the BBSRC and supported in part by the European Union Concerted Action BIOMED II (ROCIO II project).

ACKNOWLEDGMENTS

REFERENCES

REFERENCES

References

  • 1. Arenzana-Seisdedos F, Thompson J, Rodriguez M S, Bachelerie F, Thomas D, Hay R TInducible nuclear expression of newly synthesized IκBα negatively regulates DNA-binding and transcriptional activities of NF-κB. Mol Cell Biol. 1995;15:2689–2696.[Google Scholar]
  • 2. Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay R T, Virelizier J L, Dargemont CNuclear localization of IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm. J Cell Sci. 1997;110:369–378.[PubMed][Google Scholar]
  • 3. Baeuerle P A, Baltimore DNF-κB: ten years after. Cell. 1996;87:13–20.[PubMed][Google Scholar]
  • 4. Baldi L, Brown K, Franzoso G, Siebenlist UCritical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of IκBα J Biol Chem. 1996;271:376–379.[PubMed][Google Scholar]
  • 5. Baldwin A SThe NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–683.[PubMed][Google Scholar]
  • 6. Beauparlant P, Lin R T, Hiscott JThe role of the C-terminal domain of IκBα in protein degradation and stabilization. J Biol Chem. 1996;271:10690–10696.[PubMed][Google Scholar]
  • 7. Ben-David Y, Bani M R, Chabot B, De Koven A, Bernstein ARetroviral insertions downstream of the heterogeneous nuclear ribonucleoprotein A1 gene in erythroleukemia cells: evidence that A1 is not essential for cell growth. Mol Cell Biol. 1992;12:4449–4455.[Google Scholar]
  • 8. Brockman J A, Scherer D C, McKinsey T A, Hall S M, Qi X X, Lee W Y, Ballard D WCoupling of a signal response domain in IκBα to multiple pathways for NF-κB activation. Mol Cell Biol. 1995;15:2809–2818.[Google Scholar]
  • 9. Brown K, Franzoso G, Baldi L, Carlson L, Mills L, Lin Y C, Gerstberger S, Siebenlist UThe signal response of IκBα is regulated by transferable N-and C-terminal domains. Mol Cell Biol. 1997;17:3021–3027.[Google Scholar]
  • 10. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist UControl of IκBα proteolysis by site-specific, signal-induced phosphorylation. Science. 1995;267:1485–1488.[PubMed][Google Scholar]
  • 11. Buvoli M, Cobianchi F, Beśtagno M G, Mangiarotti A, Bassi M T, Biamonti G, Riva SAlternative splicing in the human gene for the core protein A1 generates another hnRNP protein. EMBO J. 1990;9:1229–1235.[Google Scholar]
  • 12. Caceres J F, Stamm S, Helfman D M, Krainer A RRegulation of alternative splicing in vivo by overexpression of antagonistic splicing factors. Science. 1994;265:1706–1709.[PubMed][Google Scholar]
  • 13. Carlotti F, Dower S K, Qwarnstrom E EDynamic shuttling of NF-κB between the nucleus and cytoplasm as a consequence of inhibitor dissociation. J Biol Chem. 2000;275:41028–41034.[PubMed][Google Scholar]
  • 14. Desterro J M P, Rodriguez M S, Kemp G D, Hay R TIdentification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem. 1999;274:10618–10624.[PubMed][Google Scholar]
  • 15. Desterro J M P, Thomson J, Hay R TUbch9 conjugates SUMO but not ubiquitin. FEBS Lett. 1997;417:297–300.[PubMed][Google Scholar]
  • 16. DiDonato J A, Hayakawa M, Rothwarf D M, Zandi E, Karin MA cytokine responsive IκB kinase that activates the transcription factor NF-κB. Nature. 1997;388:548–554.[PubMed][Google Scholar]
  • 17. Dreyfuss G, Matunis M J, Pinol-Roma S, Burd C GhnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.[PubMed][Google Scholar]
  • 18. Durfee T, Becherer K, Chen P L, Yeh S H, Yang Y, Kilburn A E, Lee W H, Elledge S JThe retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes Dev. 1993;7:555–569.[PubMed][Google Scholar]
  • 19. Fornerod M, Ohno M, Yoshida M, Mattaj I WCRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90:1051–1060.[PubMed][Google Scholar]
  • 20. Fornerod M, van Deursen J, van Baal S, Reynolds A, Davis D, Murti K G, Fransen J, Grosveld GThe human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J. 1997;16:807–816.[Google Scholar]
  • 21. Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida ECRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature. 1997;390:308–311.[PubMed][Google Scholar]
  • 22. Hanke T, Szawlowski P, Randall R EConstruction of solid matrix-antibody-antigen complexes containing simian immunodeficiency virus p27 using tag-specific monoclonal antibody and tag-linked antigen. J Gen Virol. 1992;73:653–660.[PubMed][Google Scholar]
  • 23. Harhaj E W, Sun S CRegulation of RelA subcellular localization by a putative nuclear export signal and p50. Mol Cell Biol. 1999;19:7088–7095.[Google Scholar]
  • 24. Harlow E, Lane D P Antibodies: a laboratory manual. Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory; 1988. [PubMed][Google Scholar]
  • 25. Haskill S, Beg A A, Tompkins S M, Morris J S, Yurochko A D, Sampson-Johannes A, Mondal K, Ralph P, Baldwin A SCharacterization of an immediate-early gene induced in adherent monocytes that encodes IκBα like activity. Cell. 1991;65:1281–1289.[PubMed][Google Scholar]
  • 26. Hatakeyama S, Kitagawa M, Nakayama K, Shirane M, Matsumoto M, Hattori K, Higashi H, Nakano H, Okumura K, Onoe K, Good R A, Nakayama KUbiquitin-dependent degradation of IκBα is mediated by a ubiquitin ligase Skp1/Cul 1/F-box protein FWD1. Proc Natl Acad Sci USA. 1999;96:3859–3863.[Google Scholar]
  • 27. Hay R T, Vuillard L, Desterro J M, Rodriguez M SControl of NF-κB transcriptional activation by signal induced proteolysis of IκBα Philos Trans R Soc Lond B Biol Sci. 1999;354:1601–1609.[Google Scholar]
  • 28. Huang T T, Kudo N, Yoshida M, Miyamoto SA nuclear export signal in the N-terminal regulatory domain of IκBα controls cytoplasmic localization of inactive NF-κB/IκBα complexes. Proc Natl Acad Sci USA. 2000;97:1014–1019.[Google Scholar]
  • 29. Izaurralde E, Jarmolowski A, Beisel C, Mattaj I W, Dreyfuss G, Fischer UA role for the M9 transport signal of hnRNPA1 in mRNA nuclear export. J Cell Biol. 1997;137:27–35.[Google Scholar]
  • 30. Jaffray E, Wood K M, Hay R TDomain organization of IκBα and sites of interaction with NF-κB p65. Mol Cell Biol. 1995;15:2166–2172.[Google Scholar]
  • 31. Jayaraman P S, Hirst K, Goding C RThe activation domain of a basic helix-loop-helix protein is masked by repressor interaction with domains distinct from that required for transcription regulation. EMBO J. 1994;13:2192–2199.[Google Scholar]
  • 32. Johnson C, Van Antwerp D, Hope T JAn N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα EMBO J. 1999;18:6682–6693.[Google Scholar]
  • 33. Kiledjian M, Dreyfuss GPrimary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J. 1992;11:2655–2664.[Google Scholar]
  • 34. Kroll M, Conconi M, Desterro M J, Marin A, Thomas D, Friguet B, Hay R T, Virelizier J L, Arenzana-Seisdedos F, Rodriguez M SThe carboxy terminus of IκBα determines susceptibility to degradation by the catalytic core of the proteasome. Oncogene. 1997;15:1841–1850.[PubMed][Google Scholar]
  • 35. Luque I, Zong W, Chen C, Gelinas CN-terminal determinants of IκBα necessary for the cytoplasmic regulation of c-Rel. Oncogene. 2000;19:1239–1244.[PubMed][Google Scholar]
  • 36. Mayeda A, Krainer A RRegulation of alternative pre-mRNA splicing by hnRNPA1 and splicing factor SF2. Cell. 1992;68:365–375.[PubMed][Google Scholar]
  • 37. Mayeda A, Munroe S H, Caceres J F, Krainer A RFunction of conserved domains of hnRNPA1 and other hnRNP A/B proteins. EMBO J. 1994;13:5483–5495.[Google Scholar]
  • 38. Mercurio F, Zhu H, Murray B W, Shevchenko A, Bennett B L, Li J W, Young D B, Barbosa M, Mann M, Manning A, Rao AIKK-1 and IKK-2: cytokine activated IκB kinases essential for NF-κB activation. Science. 1997;278:860–866.[PubMed][Google Scholar]
  • 39. Michael W M, Choi M, Dreyfuss GA nuclear export signal in hnRNPA1: a signal mediated, temperature dependent nuclear protein export pathway. Cell. 1995;83:415–422.[PubMed][Google Scholar]
  • 40. Michael W M, Siomi H, Choi M, Pinol-Roma S, Nakielny S, Liu Q, Dreyfuss GSignal sequences that target nuclear import and nuclear export of pre-mRNA-binding proteins. Cold Spring Harb Symp Quant Biol. 1995;60:663–668.[PubMed][Google Scholar]
  • 41. Munroe S H, Dong X F. Heterogeneous nuclear ribonucleoprotein A1 catalyzes RNA. RNA annealing. Proc Natl Acad Sci USA. 1992;89:895–899.
  • 42. Ohno H, Takimoto G, McKeithan T WThe candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination of cell cycle control. Cell. 1990;60:991–997.[PubMed][Google Scholar]
  • 43. Ohta T, Michel J J, Schottelius A J, Xiong YROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell. 1999;3:535–541.[PubMed][Google Scholar]
  • 44. Ossareh-Nazari B, Bachelerie F, Dargemont CEvidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997;278:141–144.[PubMed][Google Scholar]
  • 45. Pinol-Roma S, Dreyfuss GShuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992;355:730–732.[PubMed][Google Scholar]
  • 46. Pontius B W, Berg PRapid assembly and disassembly of complementary DNA strands through an equilibrium intermediate state mediated by A1 hnRNP protein. J Biol Chem. 1992;267:13815–13818.[PubMed][Google Scholar]
  • 47. Regnier C H, Song H Y, Gao X, Goeddel D V, Cao Z D, Rothe MIdentification and characterization of an IκB kinase. Cell. 1997;90:373–383.[PubMed][Google Scholar]
  • 48. Renard P, Percherancier Y, Kroll M, Thomas D, Virelizier J L, Arenzana-Seisdedos F, Bachelerie FInducible NF-κB activation is permitted by simultaneous degradation of nuclear IκBα J Biol Chem. 2000;275:15193–15199.[PubMed][Google Scholar]
  • 49. Rodriguez M S, Michalopoulos I, Arenzanaseisdedos F, Hay R TInducible degradation of IκBα in vitro and in vivo requires the acidic C-terminal domain of the protein. Mol Cell Biol. 1995;15:2413–2419.[Google Scholar]
  • 50. Rodriguez M S, Thompson J, Hay R T, Dargemont CNuclear retention of IκBα protects it from signal-induced degradation and inhibits NF-κB transcriptional activation. J Biol Chem. 1999;274:9108–9115.[PubMed][Google Scholar]
  • 51. Rodriguez M S, Wright J, Thompson J, Thomas D, Baleux F, Virelizier J L, Hay R T, Arenzana-Seisdedos FIdentification of lysine residues required for signal-induced ubiquitination and degradation of IκBα in vivo. Oncogene. 1996;12:2425–2435.[PubMed][Google Scholar]
  • 52. Roff M, Thomson J, Rodriguez M S, Jacque J-M, Baleux F, Arenzana-Seisdedos F, Hay R TRole of IκBα ubiquitination in signal-induced activation of NF-κB in vivo. J Biol Chem. 1996;271:7844–7850.[PubMed][Google Scholar]
  • 53. Sachdev S, Bagchi S, Zhang D D, Mings A C, Hannink MNuclear import of IκBα is accomplished by a ran-independent transport pathway. Mol Cell Biol. 2000;20:1571–1582.[Google Scholar]
  • 54. Sachdev S, Hoffmann A, Hannink MNuclear localization of IκBα is mediated by the second ankyrin repeat: the IκBα ankyrin repeats define a novel class of cis-acting nuclear import sequences. Mol Cell Biol. 1998;18:2524–2534.[Google Scholar]
  • 55. Scherer D C, Brockman J A, Chen Z, Maniatis T, Ballard D WSignal-induced degradation of IκBα requires site-specific ubiquitination. Proc Natl Acad Sci USA. 1995;92:11259–11263.[Google Scholar]
  • 56. Spencer E, Jiang J, Chen Z JSignal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP. Genes Dev. 1999;13:284–294.[Google Scholar]
  • 57. Stade K, Ford C S, Guthrie C, Weis KExportin 1 (Crm1p) is an essential nuclear export factor. Cell. 1997;90:1041–1050.[PubMed][Google Scholar]
  • 58. Stark L A, Hay R THuman immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) interacts with Lys-tRNA synthetase: implications for priming of HIV-1 reverse transcription. J Virol. 1998;72:3037–3044.[Google Scholar]
  • 59. Sun S C, Elwood J, Greene W CBoth amino-terminal and carboxyl-terminal sequences within IκBα regulate its inducible degradation. Mol Cell Biol. 1996;16:1058–1065.[Google Scholar]
  • 60. Sylla B S, Hung S C, Davidson D M, Hatzivassiliou E, Malinin N L, Wallach D, Gilmore T D, Kieff E, Mosialos GEpstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-κB through a pathway that includes the NF-κB-inducing kinase and the IκB kinases IKKalpha and IKKbeta. Proc Natl Acad Sci USA. 1998;95:10106–10111.[Google Scholar]
  • 61. Tam W F, Lee L H, Davis L, Sen RCytoplasmic sequestration of rel proteins by IκBα requires CRM1-dependent nuclear export. Mol Cell Biol. 2000;20:2269–2284.[Google Scholar]
  • 62. Tan P, Fuchs S Y, Chen A, Wu K, Gomez C, Ronai Z, Pan Z QRecruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of IκBα Mol Cell. 1999;3:527–533.[PubMed][Google Scholar]
  • 63. Thompson J E, Phillips R J, Erdjument-Bromage H, Tempst P, Ghosh SIκBβ regulates the persistent response in a biphasic activation of NF-κB. Cell. 1995;80:573–582.[PubMed][Google Scholar]
  • 64. Traenckner EBM, Pahl H L, Henkel T, Schmidt K N, Wilk S, Baeuerle P APhosphorylation of human IκBα on serine 32 and serine 36 controls IκBα proteolysis and NF-κB activation in response to diverse stimuli. EMBO J. 1995;14:2876–2883.[Google Scholar]
  • 65. Turpin P, Hay R T, Dargemont CCharacterisation of the IκBα nuclear import pathway. J Biol Chem. 1999;274:6804–6812.[PubMed][Google Scholar]
  • 66. Visa N, Alzhanova-Ericsson A T, Sun X, Kiseleva E, Bjorkroth B, Wurtz T, Daneholt BA pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell. 1996;84:253–264.[PubMed][Google Scholar]
  • 67. Vuillard L, Nicholson J, Hay R TA complex containing β-TrCP recruits Cdc34 to catalyse ubiquitination of IκBα FEBS Lett. 1999;455:311–314.[PubMed][Google Scholar]
  • 68. Whiteside S T, Epinat J-C, Rice N R, Israel AIκB epsilon, a novel member of the IκB family, controls RelA and c-Rel NF-κB activity. EMBO J. 1997;16:1413–1426.[Google Scholar]
  • 69. Whiteside S T, Ernst M K, Lebail O, Laurentwinter C, Rice N, Israel AN-terminal and C-terminal sequences control degradation of Mad3/IκBα in response to inducers of NF-κB activity. Mol Cell Biol. 1995;15:5339–5345.[Google Scholar]
  • 70. Winston J T, Strack P, Beer-Romero P, Chu C Y, Elledge S J, Harper J WThe SCF β-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev. 1999;13:270–283.[Google Scholar]
  • 71. Woronicz J D, Gao X, Cao Z, Rothe M, Goeddel D VIκB kinase-beta: NF-κB activation and complex formation with IκB kinase-alpha and NIK. Science. 1997;278:866–869.[PubMed][Google Scholar]
  • 72. Xu R M, Jokhan L, Cheng X, Mayeda A, Krainer A RCrystal structure of human UP1, the domain of hnRNPA1 that contains two RNA-recognition motifs. Structure. 1997;5:559–570.[PubMed][Google Scholar]
  • 73. Yang X, Bani M R, Lu S J, Rowan S, Ben-David Y, Chabot BThe A1 and A1B proteins of heterogeneous nuclear ribonucleoparticles modulate 5′ splice site selection in vivo. Proc Natl Acad Sci USA. 1994;91:6924–6928.[Google Scholar]
  • 74. Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning A M, Andersen J S, Mann M, Mercurio F, Ben-Neriah YIdentification of the receptor component of the IκBα-ubiquitin ligase. Nature. 1998;396:590–594.[PubMed][Google Scholar]
  • 75. Zandi E, Rothwarf D M, Delhase M, Hayakawa M, Karin MThe IκB kinase complex (IKK) contains two kinase subunits, IKK alpha and IKK beta, necessary for IκB phosphorylation and NF-κB activation. Cell. 1997;91:243–252.[PubMed][Google Scholar]
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