This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ernst, M. K. Articles by Rice, N. R. Search for Related Content PubMed PubMed Citation Articles by Ernst, M. K. Articles by Rice, N. R.

 Previous Article  |  Next Article 

Mol. Cell. Biol., 02 1995, 872-882, Vol 15, No. 2
Copyright © 1995, American Society for Microbiology

The PEST-like sequence of I kappa B alpha is responsible for inhibition of DNA binding but not for cytoplasmic retention of c-Rel or RelA homodimers

MK Ernst, LL Dunn and NR Rice
Laboratory of Molecular Virology and Carcinogenesis, National Cancer Institute Frederick Cancer Research and Development Center, Maryland 21702-1201.

In most cells, proteins belonging to the Rel/NF-kappa B family of transcription factors are held in inactive form in the cytoplasm by an inhibitor protein, I kappa B alpha. Stimulation of the cells leads to degradation of the inhibitor and transit of active DNA-binding Rel/NF- kappa B dimers to the nucleus. I kappa B alpha is also able to inhibit DNA binding by Rel/NF-kappa B dimers in vitro, suggesting that it may perform the same function in cells when the activating signal is no longer present. Structurally, the human I kappa B alpha molecule can be divided into three sections: a 70-amino-acid N terminus with no known function, a 205-residue midsection composed of six ankyrin-like repeats, and a very acidic 42-amino-acid C terminus that resembles a PEST sequence. In this study we examined how the structural elements of the I kappa B alpha protein correlate with its functional capabilities both in vitro and in vivo. Using a battery of I kappa B alpha mutants, we show that (i) a dimer binds a single I kappa B alpha molecule, (ii) the acidic C-terminal region of I kappa B alpha is not required for protein-protein binding and does not mask the nuclear localization signal of the dimer, (iii) the same C-terminal region is required for inhibition of DNA binding, and (iv) this inhibition may be accomplished by direct interaction between the PEST-like region and the DNA-binding region of one of the subunits of the dimer.

This article has been cited by other articles:

• Zhou, H.-J., Pham, L. V., Tamayo, A. T., Lin-Lee, Y.-C., Fu, L., Yoshimura, L. C., Ford, R. J. (2007). Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma. Blood 110: 2121-2127 [Abstract] [Full Text]  
• Wang, X. W., Tan, N. S., Ho, B., Ding, J. L. (2006). Evidence for the ancient origin of the NF-{kappa}B/I{kappa}B cascade: Its archaic role in pathogen infection and immunity.. Proc. Natl. Acad. Sci. USA 103: 4204-4209 [Abstract] [Full Text]  
• LU, N. Z., CIDLOWSKI, J. A. (2004). The Origin and Functions of Multiple Human Glucocorticoid Receptor Isoforms. Ann. N. Y. Acad. Sci. 1024: 102-123 [Abstract] [Full Text]  
• Fu, D., Kobayashi, M., Lin, L. (2004). A p105-based Inhibitor Broadly Represses NF-{kappa}B Activities. J. Biol. Chem. 279: 12819-12826 [Abstract] [Full Text]  
• Dobrovolskaia, M. A., Medvedev, A. E., Thomas, K. E., Cuesta, N., Toshchakov, V., Ren, T., Cody, M. J., Michalek, S. M., Rice, N. R., Vogel, S. N. (2003). Induction of In Vitro Reprogramming by Toll-Like Receptor (TLR)2 and TLR4 Agonists in Murine Macrophages: Effects of TLR "Homotolerance" Versus "Heterotolerance" on NF-{kappa}B Signaling Pathway Components. J. Immunol. 170: 508-519 [Abstract] [Full Text]  
• Wallace, A. D., Cidlowski, J. A. (2001). Proteasome-mediated Glucocorticoid Receptor Degradation Restricts Transcriptional Signaling by Glucocorticoids. J. Biol. Chem. 276: 42714-42721 [Abstract] [Full Text]  
• Baetu, T. M., Kwon, H., Sharma, S., Grandvaux, N., Hiscott, J. (2001). Disruption of NF-{kappa}B Signaling Reveals a Novel Role for NF-{kappa}B in the Regulation of TNF-Related Apoptosis-Inducing Ligand Expression. J. Immunol. 167: 3164-3173 [Abstract] [Full Text]  
• Jungnickel, B., Staratschek-Jox, A., Brauninger, A., Spieker, T., Wolf, J., Diehl, V., Hansmann, M.-L., Rajewsky, K., Kuppers, R. (2000). Clonal Deleterious Mutations in the I{kappa}B{alpha} Gene in the Malignant Cells in Hodgkin's Lymphoma. J. Exp. Med. 191: 395-402 [Abstract] [Full Text]  
• Emmerich, F., Meiser, M., Hummel, M., Demel, G., Foss, H.-D., Jundt, F., Mathas, S., Krappmann, D., Scheidereit, C., Stein, H., Dorken, B. (1999). Overexpression of I Kappa B Alpha Without Inhibition of NF-kappa B Activity and Mutations in the I Kappa B Alpha Gene in Reed-Sternberg Cells. Blood 94: 3129-3134 [Abstract] [Full Text]  
• Shumway, S. D., Maki, M., Miyamoto, S. (1999). The PEST Domain of Ikappa Balpha Is Necessary and Sufficient for in Vitro Degradation by {micro}-Calpain. J. Biol. Chem. 274: 30874-30881 [Abstract] [Full Text]  
• Algarte, M., Kwon, H., Genin, P., Hiscott, J. (1999). Identification by In Vivo Genomic Footprinting of a Transcriptional Switch Containing NF-kappa B and Sp1 That Regulates the Ikappa Balpha Promoter. Mol. Cell. Biol. 19: 6140-6153 [Abstract] [Full Text]  
• Han, Y., Runge, M. S., Brasier, A. R. (1999). Angiotensin II Induces Interleukin-6 Transcription in Vascular Smooth Muscle Cells Through Pleiotropic Activation of Nuclear Factor-{kappa}B Transcription Factors. Circ. Res. 84: 695-703 [Abstract] [Full Text]  
• Simeonidis, S., Stauber, D., Chen, G., Hendrickson, W. A., Thanos, D. (1999). Mechanisms by which Ikappa B proteins control NF-kappa B activity. Proc. Natl. Acad. Sci. USA 96: 49-54 [Abstract] [Full Text]  
• 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-kappa B. J. Biol. Chem. 273: 25427-25435 [Abstract] [Full Text]  
• Sachdev, S., Hoffmann, A., Hannink, M. (1998). Nuclear Localization of Ikappa Balpha Is Mediated by the Second Ankyrin Repeat: the Ikappa Balpha Ankyrin Repeats Define a Novel Class of cis-Acting Nuclear Import Sequences. Mol. Cell. Biol. 18: 2524-2534 [Abstract] [Full Text]  
• Latimer, M., Ernst, M. K., Dunn, L. L., Drutskaya, M., Rice, N. R. (1998). The N-Terminal Domain of Ikappa Balpha Masks the Nuclear Localization Signal(s) of p50 and c-Rel Homodimers. Mol. Cell. Biol. 18: 2640-2649 [Abstract] [Full Text]  
• Kwon, H., Pelletier, N., DeLuca, C., Genin, P., Cisternas, S., Lin, R., Wainberg, M. A., Hiscott, J. (1998). Inducible Expression of Ikappa Balpha Repressor Mutants Interferes with NF-kappa B Activity and HIV-1 Replication in Jurkat T Cells. J. Biol. Chem. 273: 7431-7440 [Abstract] [Full Text]  
• Luque, I., Gélinas, C. (1998). Distinct Domains of Ikappa Balpha Regulate c-Rel in the Cytoplasm and in the Nucleus. Mol. Cell. Biol. 18: 1213-1224 [Abstract] [Full Text]  
• Bundy, D. L., McKeithan, T. W. (1997). Diverse Effects of BCL3 Phosphorylation on Its Modulation of NF-kappa B p52 Homodimer Binding to DNA. J. Biol. Chem. 272: 33132-33139 [Abstract] [Full Text]  
• Simeonidis, S., Liang, S., Chen, G., Thanos, D. (1997). Cloning and functional characterization of mouse Ikappa Bvarepsilon. Proc. Natl. Acad. Sci. USA 94: 14372-14377 [Abstract] [Full Text]  
• Palmer, G. H., Machado, J. Jr., Fernandez, P., Heussler, V., Perinat, T., Dobbelaere, D. A. E. (1997). Parasite-mediated nuclear factor kappa B regulation in lymphoproliferation caused by Theileria parva infection. Proc. Natl. Acad. Sci. USA 94: 12527-12532 [Abstract] [Full Text]  
• Weil, R., Laurent-Winter, C., Israel, A. (1997). Regulation of Ikappa Bbeta Degradation. SIMILARITIES TO AND DIFFERENCES FROM Ikappa Balpha. J. Biol. Chem. 272: 9942-9949 [Abstract] [Full Text]  
• Beauparlant, P., Lin, R., Hiscott, J. (1996). The Role of the C-terminal Domain of IkappaBalpha in Protein Degradation and Stabilization. J. Biol. Chem. 271: 10690-10696 [Abstract] [Full Text]  
• Baldi, L., Brown, K., Franzoso, G., Siebenlist, U. (1996). Critical Role for Lysines 21 and 22 in Signal-induced, Ubiquitin-mediated Proteolysis of IkappaB-alpha. J. Biol. Chem. 271: 376-379 [Abstract] [Full Text]  
• Kuno, K., Ishikawa, Y., Ernst, M. K., Ogata, M., Rice, N. R., Mukaida, N., Matsushima, K. (1995). Identification of an IkappaBalpha-associated Protein Kinase in a Human Monocytic Cell Line and Determination of Its Phosphorylation Sites on IkappaBalpha. J. Biol. Chem. 270: 27914-27919 [Abstract] [Full Text]  
• Verma, I M, Stevenson, J K, Schwarz, E M, Van Antwerp, D, Miyamoto, S (1995). Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation.. Genes Dev. 9: 2723-2735  
• Chen, Z, Hagler, J, Palombella, V J, Melandri, F, Scherer, D, Ballard, D, Maniatis, T (1995). Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.. Genes Dev. 9: 1586-1597 [Abstract]  
• Malek, S., Chen, Y., Huxford, T., Ghosh, G. (2001). Ikappa Bbeta , but Not Ikappa Balpha , Functions as a Classical Cytoplasmic Inhibitor of NF-kappa B Dimers by Masking Both NF-kappa B Nuclear Localization Sequences in Resting Cells. J. Biol. Chem. 276: 45225-45235 [Abstract] [Full Text]