Distinct Domains of IκBα Regulate c-Rel in the Cytoplasm and in the Nucleus

REFERENCES

• Alkalay, I., A. Yaron, A. Hatzubai, A. Orian, A. Ciechanover, and Y. Ben-Neriah 1995. Stimulation-dependent IκBα phosphorylation marks the NF-κB inhibitor for degradation via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA 92: 10599–10603.
   PubMed Web of Science ®Google Scholar
• Aoki, T., Y. Sano, T. Yamamoto, and J. I. Inoue 1996. The ankyrin repeats but not the PEST-like sequences are required for signal-dependent degradation of IκBα. Oncogene 12: 1159–1164.
   PubMedGoogle Scholar
• Arenzana-Seisdedos, F., J. Thompson, M. S. Rodriguez, F. Bachelerie, D. Thomas, and R. T. Hay 1995. Inducible nuclear expression of newly synthesized IκBα negatively regulates DNA-binding and transcriptional activities of NF-κB. Mol. Cell. Biol. 15: 2689–2696.
   PubMed Web of Science ®Google Scholar
• Arenzana-Seisdedos, F., P. Turpin, M. Rodriguez, D. Thomas, R. T. Hay, J. L. Virelizier, and C. Dargemont 1997. Nuclear localization of IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm. J. Cell Sci. 110: 369–378.
   PubMedGoogle Scholar
• Baeuerle, P. A., and D. Baltimore 1989. A 65-kD subunit of active NF-κB is required for inhibition of NF-κB by IκB. Genes Dev. 3: 1689–1698.
   PubMed Web of Science ®Google Scholar
• Baeuerle, P. A., and T. Henkel 1994. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12: 141–179.
   PubMed Web of Science ®Google Scholar
• Baldwin, A. S.Jr. 1996. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14: 649–683.
   PubMed Web of Science ®Google Scholar
• Barroga, C. F., J. K. Stevenson, E. M. Schwarz, and I. M. Verma 1995. Constitutive phosphorylation of IκBα by casein kinase II. Proc. Natl. Acad. Sci. USA 92: 7637–7641.
   PubMed Web of Science ®Google Scholar
• Beauparlant, P., R. Lin, and J. Hiscott 1996. The role of the C-terminal domain of IκBα in protein degradation and stabilization. J. Biol. Chem. 271: 10690–10696.
   PubMedGoogle Scholar
• Beg, A. A., S. M. Ruben, R. I. Scheinman, S. Haskill, C. A. Rosen, Baldwin A. S., Jr. 1992. IκB interacts with the nuclear localization sequences of the subunits of NF-κB: a mechanism for cytoplasmic retention. Genes Dev. 6: 1899–1913.
   PubMed Web of Science ®Google Scholar
• Beg, A. A., W. C. Sha, R. T. Bronson, and D. Baltimore 1995. Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice. Genes Dev. 9: 2736–2746.
   PubMed Web of Science ®Google Scholar
• Boothby, M. R., A. L. Mora, D. C. Scherer, J. A. Brockman, and D. W. Ballard 1997. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-κB. J. Exp. Med. 185: 1897–1907.
   PubMed Web of Science ®Google Scholar
• Bours, V., G. Franzoso, V. Azarenko, S. Park, T. Kanno, K. Brown, and U. Siebenlist 1993. The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers. Cell 72: 729–739.
   PubMed Web of Science ®Google Scholar
• Bradford, M. M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.
   PubMed Web of Science ®Google Scholar
• Brockman, J. A., D. C. Scherer, T. A. McKinsey, S. M. Hall, X. Qi, W. Y. Lee, and D. W. Ballard 1995. Coupling of a signal response domain in IκBα to multiple pathways for NF-κB activation. Mol. Cell. Biol. 15: 2809–2818.
   PubMed Web of Science ®Google Scholar
• Brown, K., S. Gerstberger, L. Carlson, G. Franzoso, and U. Siebenlist 1995. Control of IκB-α proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485–1488.
   PubMed Web of Science ®Google Scholar
• Brown, K., S. Park, T. Kanno, G. Franzoso, and U. Siebenlist 1993. Mutual regulation of the transcriptional activator NF-κB and its inhibitor, IκB-α. Proc. Natl. Acad. Sci. USA 90: 2532–2536.
   PubMed Web of Science ®Google Scholar
• Capobianco, A. J., D. L. Simmons, and T. D. Gilmore 1990. Cloning and expression of a chicken c-rel cDNA: unlike p59v-rel, p68c-rel is a cytoplasmic protein in chicken embryo fibroblasts. Oncogene 5: 257–265.
   PubMedGoogle Scholar
• Chen, C., and H. Okayama 1987. High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7: 2745–2752.
   PubMed Web of Science ®Google Scholar
• Chen, Z., J. Hagler, V. J. Palombella, F. Melandri, D. Scherer, D. Ballard, and T. Maniatis 1995. Signal-induced site-specific phosphorylation targets IκBα to the ubiquitin-proteasome pathway. Genes Dev. 9: 1586–1597.
   PubMed Web of Science ®Google Scholar
• Chiao, P. J., S. Miyamoto, and I. M. Verma 1994. Autoregulation of IκBα activity. Proc. Natl. Acad. Sci. USA 91: 28–32.
   PubMed Web of Science ®Google Scholar
• Chu, Z. L., T. A. McKinsey, L. Liu, X. Qi, and D. W. Ballard 1996. Basal phosphorylation of the PEST domain in IκBβ regulates its functional interaction with the c-rel proto-oncogene product. Mol. Cell. Biol. 16: 5974–5984.
   PubMedGoogle Scholar
• Davis, N., S. Ghosh, D. L. Simmons, P. Tempst, H. C. Liou, D. Baltimore, Bose H. R., Jr. 1991. Rel-associated pp40: an inhibitor of the rel family of transcription factors. Science 253: 1268–1271.
   PubMedGoogle Scholar
• Diehl, J. A., W. Tong, G. Sun, and M. Hannink 1995. Tumor necrosis factor-α-dependent activation of a RelA homodimer in astrocytes. Increased phosphorylation of RelA and MAD-3 precedes activation of RelA. J. Biol. Chem. 270: 2703–2707.
   PubMedGoogle Scholar
• Dougherty, J. P., R. Wisniewski, S. L. Yang, B. W. Rhode, and H. M. Temin 1989. New retrovirus helper cells with almost no nucleotide sequence homology to retrovirus vectors. J. Virol. 63: 3209–3212.
   PubMed Web of Science ®Google Scholar
• Ernst, M. K., L. L. Dunn, and N. R. Rice 1995. The PEST-like sequence of IκBα is responsible for inhibition of DNA binding but not for cytoplasmic retention of c-Rel or RelA homodimers. Mol. Cell. Biol. 15: 872–882.
   PubMedGoogle Scholar
• Fujita, T., G. P. Nolan, H. C. Liou, M. L. Scott, and D. Baltimore 1993. The candidate proto-oncogene bcl-3 encodes a transcriptional coactivator that activates through NF-κB p50 homodimers. Genes Dev. 7: 1354–1363.
   PubMed Web of Science ®Google Scholar
• Ganchi, P. A., S. C. Sun, W. C. Greene, and D. W. Ballard 1992. IκB/MAD-3 masks the nuclear localization signal of NF-κB p65 and requires the transactivation domain to inhibit NF-κB p65 DNA binding. Mol. Biol. Cell 3: 1339–1352.
   PubMedGoogle Scholar
• Gélinas, C., and H. M. Temin 1988. The v-rel oncogene encodes a cell-specific transcriptional activator of certain promoters. Oncogene 3: 349–355.
   PubMedGoogle Scholar
• Ghosh, G., G. van Duyne, S. Ghosh, and P. B. Sigler 1995. Structure of NF-κB p50 homodimer bound to a κB site. Nature (London) 373: 303–310.
   PubMed Web of Science ®Google Scholar
• Gilmore, T. D., M. Koedood, K. A. Piffat, and D. W. White 1996. Rel/NF-κB/IκB proteins and cancer. Oncogene 13: 1367–1378.
   PubMed Web of Science ®Google Scholar
• Gilmore, T. D., and P. J. Morin 1993. The IκB proteins: members of a multifunctional family. Trends Genet. 9: 427–433.
   PubMed Web of Science ®Google Scholar
• Govind, S., E. Drier, L. H. Huang, and R. Steward 1996. Regulated nuclear import of the Drosophila Rel protein Dorsal: structure-function analysis. Mol. Cell. Biol. 16: 1103–1114.
   PubMedGoogle Scholar
• Haskill, S., A. A. Beg, S. M. Tompkins, J. S. Morris, A. D. Yurochko, A. Sampson-Johannes, K. Mondal, P. Ralph, Baldwin A. S., Jr. 1991. Characterization of an immediate-early gene induced in adherent monocytes that encodes IκB-like activity. Cell 65: 1281–1289.
   PubMed Web of Science ®Google Scholar
• Hatada, E. N., M. Naumann, and C. Scheidereit 1993. Common structural constituents confer IκB activity to NF-κB p105 and IκB/MAD-3. EMBO J. 12: 2781–2788.
   PubMedGoogle Scholar
• Inoue, J., L. D. Kerr, D. Rashid, N. Davis, Bose H. R., Jr., and I. M. Verma 1992. Direct association of pp40/IκBβ with rel/NF-κB transcription factors: role of ankyrin repeats in the inhibition of DNA binding activity. Proc. Natl. Acad. Sci. USA 89: 4333–4337.
   PubMedGoogle Scholar
• Jaffray, E., K. M. Wood, and R. T. Hay 1995. Domain organization of IκBα and sites of interaction with NF-κB p65. Mol. Cell. Biol. 15: 2166–2172.
   PubMedGoogle Scholar
• Kalderon, D., B. L. Roberts, W. D. Richardson, and A. E. Smith 1984. A short amino acid sequence able to specify nuclear location. Cell 39: 499–509.
   PubMed Web of Science ®Google Scholar
• Kerr, L. D., J. Inoue, N. Davis, E. Link, P. A. Baeuerle, Bose H. R., Jr., and I. M. Verma 1991. The Rel-associated pp40 protein prevents DNA binding of Rel and NF-κB: relationship with IκBβ and regulation by phosphorylation. Genes Dev. 5: 1464–1476.
   PubMedGoogle Scholar
• Kerr, L. D., L. J. Ransone, P. Wamsley, M. J. Schmitt, T. G. Boyer, Q. Zhou, A. J. Berk, and I. M. Verma 1993. Association between proto-oncoprotein Rel and TATA-binding protein mediates transcriptional activation by NF-κB. Nature (London) 365: 412–419.
   PubMedGoogle Scholar
• Klement, J. F., N. R. Rice, B. D. Car, S. J. Abbondanzo, G. D. Powers, P. H. Bhatt, C. H. Chen, C. A. Rosen, and C. L. Stewart 1996. IκBα deficiency results in a sustained NF-κB response and severe widespread dermatitis in mice. Mol. Cell. Biol. 16: 2341–2349.
   PubMed Web of Science ®Google Scholar
• Kontgen, F., R. J. Grumont, A. Strasser, D. Metcalf, R. Li, D. Tarlinton, and S. Gerondakis 1995. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 9: 1965–1977.
   PubMed Web of Science ®Google Scholar
• Krappmann, D., F. G. Wulczyn, and C. Scheidereit 1996. Different mechanisms control signal-induced degradation and basal turnover of the NF-κB inhibitor IκBα in vivo. EMBO J. 15: 6716–6726.
   PubMed Web of Science ®Google Scholar
• Kretzschmar, M., M. Meisterernst, C. Scheidereit, G. Li, and R. G. Roeder 1992. Transcriptional regulation of the HIV-1 promoter by NF-κB in vitro. Genes Dev. 6: 761–774.
   PubMed Web of Science ®Google Scholar
• Kumar, S., and C. Gélinas 1993. IκBα-mediated inhibition of v-Rel DNA binding requires direct interaction with the RXXRXRXXC Rel/κB DNA-binding motif. Proc. Natl. Acad. Sci. USA 90: 8962–8966.
   PubMedGoogle Scholar
• LeBail, O., R. Schmidt-Ullrich, and A. Israël 1993. Promoter analysis of the gene encoding the IκB-α/MAD3 inhibitor of NF-κB: positive regulation by members of the rel/NF-κB family. EMBO J. 12: 5043–5049.
   PubMedGoogle Scholar
• Lehming, N., S. McGuire, J. M. Brickman, and M. Ptashne 1995. Interactions of a Rel protein with its inhibitor. Proc. Natl. Acad. Sci. USA 92: 10242–10246.
   PubMedGoogle Scholar
• Lin, R., P. Beauparlant, C. Makris, S. Meloche, and J. Hiscott 1996. Phosphorylation of IκBα in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability. Mol. Cell. Biol. 16: 1401–1409.
   PubMedGoogle Scholar
• Luque, I., and C. Gélinas 1997. Rel/NF-κB and IκB factors in oncogenesis. Semin. Cancer Biol. 8: 103–111.
   PubMed Web of Science ®Google Scholar
• Maggirwar, S. B., E. Harhaj, and S. C. Sun 1995. Activation of NF-κB/Rel by Tax involves degradation of IκBα and is blocked by a proteasome inhibitor. Oncogene 11: 993–998.
   PubMedGoogle Scholar
• McElhinny, J. A., S. A. Trushin, G. D. Bren, N. Chester, and C. V. Paya 1996. Casein kinase II phosphorylates IκBα at S-283, S-289, S-293, and T-291 and is required for its degradation. Mol. Cell. Biol. 16: 899–906.
   PubMed Web of Science ®Google Scholar
• Miyamoto, S., and I. M. Verma 1995. Rel/NF-κB/IκB story. Adv. Cancer Res. 66: 255–292.
   PubMed Web of Science ®Google Scholar
• Muller, C. W., F. A. Rey, M. Sodeoka, G. L. Verdine, and S. C. Harrison 1995. Structure of the NF-κB p50 homodimer bound to DNA. Nature (London) 373: 311–317.
   PubMed Web of Science ®Google Scholar
• Nakayama, K., H. Shimizu, K. Mitomo, T. Watanabe, S. Okamoto, and K. Yamamoto 1992. A lymphoid cell-specific nuclear factor containing c-Rel-like proteins preferentially interacts with interleukin-6 κB-related motifs whose activities are repressed in lymphoid cells. Mol. Cell. Biol. 12: 1736–1746.
   PubMedGoogle Scholar
• Osborn, L., S. Kunkel, and G. J. Nabel 1989. Tumor necrosis factor α and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor κB. Proc. Natl. Acad. Sci. USA 86: 2336–2340.
   PubMed Web of Science ®Google Scholar
• Read, M. A., A. S. Neish, M. E. Gerritsen, and T. Collins 1996. Postinduction transcriptional repression of E-selectin and vascular cell adhesion molecule-1. J. Immunol. 157: 3472–3479.
   PubMed Web of Science ®Google Scholar
• Resnitzky, D., M. Gossen, H. Bujard, and S. I. Reed 1994. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol. Cell. Biol. 14: 1669–1679.
   PubMed Web of Science ®Google Scholar
• Rice, N. Personal communication.
   Google Scholar
• Rodriguez, M. S., J. Wright, J. Thompson, D. Thomas, F. Baleux, J. L. Virelizier, R. T. Hay, and F. Arenzana-Seisdedos 1996. Identification of lysine residues required for signal-induced ubiquitination and degradation of IκB-α in vivo. Oncogene 12: 2425–2435.
   PubMed Web of Science ®Google Scholar
• Roff, M., J. Thompson, M. S. Rodriguez, J. M. Jacque, F. Baleux, F. Arenzana-Seisdedos, and R. T. Hay 1996. Role of IκBα ubiquitination in signal-induced activation of NF-κB in vivo. J. Biol. Chem. 271: 7844–7850.
   PubMed Web of Science ®Google Scholar
• Rottjakob, E. M., S. Sachdev, C. A. Leanna, T. A. McKinsey, and M. Hannink 1996. PEST-dependent cytoplasmic retention of v-Rel by IκB-α: evidence that IκB-α regulates cellular localization of c-Rel and v-Rel by distinct mechanisms. J. Virol. 70: 3176–3188.
   PubMedGoogle Scholar
• Sachdev, S., E. M. Rottjakob, J. A. Diehl, and M. Hannink 1995. IκB-α-mediated inhibition of nuclear transport and DNA-binding by Rel proteins are separable functions: phosphorylation of C-terminal serine residues of IκB-α is specifically required for inhibition of DNA-binding. Oncogene 11: 811–823.
   PubMedGoogle Scholar
• Scherer, D. C., J. A. Brockman, Z. Chen, T. Maniatis, and D. W. Ballard 1995. Signal-induced degradation of IκBα requires site-specific ubiquitination. Proc. Natl. Acad. Sci. USA 92: 11259–11263.
   PubMed Web of Science ®Google Scholar
• Schwarz, E. M., D. Van Antwerp, and I. M. Verma 1996. Constitutive phosphorylation of IκBα by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IκBα. Mol. Cell. Biol. 16: 3554–3559.
   PubMedGoogle Scholar
• Scott, M. L., T. Fujita, H. C. Liou, G. P. Nolan, and D. Baltimore 1993. The p65 subunit of NF-κB regulates IκB by two distinct mechanisms. Genes Dev. 7: 1266–1276.
   PubMed Web of Science ®Google Scholar
• Sun, S., J. Elwood, and W. C. Greene 1996. Both amino- and carboxyl-terminal sequences within IκBα regulate its inducible degradation. Mol. Cell. Biol. 16: 1058–1065.
   PubMed Web of Science ®Google Scholar
• Sun, S. C., P. A. Ganchi, D. W. Ballard, and W. C. Greene 1993. NF-κB controls expression of inhibitor IκBα: evidence for an inducible autoregulatory pathway. Science 259: 1912–1915.
   PubMed Web of Science ®Google Scholar
• Suyang, H., R. Phillips, I. Douglas, and S. Ghosh 1996. Role of unphosphorylated, newly synthesized IκBβ in persistent activation of NF-κB. Mol. Cell. Biol. 16: 5444–5449.
   PubMed Web of Science ®Google Scholar
• Thanos, D., and T. Maniatis 1995. NF-κB: a lesson in family values. Cell 80: 529–532.
   PubMed Web of Science ®Google Scholar
• Traenckner, E. B., H. L. Pahl, T. Henkel, K. N. Schmidt, S. Wilk, and P. A. Baeuerle 1995. Phosphorylation of human IκB-α on serines 32 and 36 controls IκB-α proteolysis and NF-κB activation in response to diverse stimuli. EMBO J. 14: 2876–2883.
   PubMed Web of Science ®Google Scholar
• Tran, K., M. Merika, and D. Thanos 1997. Distinct functional properties of IκBα and IκBβ. Mol. Cell. Biol. 17: 5386–5399.
   PubMedGoogle Scholar
• Van Antwerp, D. J., and I. M. Verma 1996. Signal-induced degradation of IκBα: association with NF-κB and the PEST sequence in IκBα are not required. Mol. Cell. Biol. 16: 6037–6045.
   PubMed Web of Science ®Google Scholar
• Verma, I. M., J. K. Stevenson, E. M. Schwarz, D. Van Antwerp, and S. Miyamoto 1995. Rel/NF-κB/IκB family: intimate tales of association and dissociation. Genes Dev. 9: 2723–2735.
   PubMed Web of Science ®Google Scholar
• Whiteside, S. T., M. K. Ernst, O. LeBail, C. Laurent-Winter, N. Rice, and A. Israël 1995. N- and C-terminal sequences control degradation of MAD3/IκBα in response to inducers of NF-κB activity. Mol. Cell. Biol. 15: 5339–5345.
   PubMed Web of Science ®Google Scholar
• Xu, X., and C. Gélinas 1997. A mutant Rel-homology domain promotes transcription by p50/NFκB1. Oncogene 14: 1521–1530.
   PubMedGoogle Scholar
• Xu, X., C. Prorock, H. Ishikawa, E. Maldonado, Y. Ito, and C. Gélinas 1993. Functional interaction of the v-Rel and c-Rel oncoproteins with the TATA-binding protein and association with transcription factor IIB. Mol. Cell. Biol. 13: 6733–6741.
   PubMedGoogle Scholar
• Zabel, U., and P. A. Baeuerle 1990. Purified human IκB can rapidly dissociate the complex of the NF-κB transcription factor with its cognate DNA. Cell 61: 255–265.
   PubMed Web of Science ®Google Scholar
• Zabel, U., T. Henkel, M. S. Silva, and P. A. Baeuerle 1993. Nuclear uptake control of NF-κB by MAD-3, an IκB protein present in the nucleus. EMBO J. 12: 201–211.
   PubMedGoogle Scholar