IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.[5] In addition, IκBα blocks the ability of NF-κB transcription factors to bind to DNA, which is required for NF-κB's proper functioning.[6]
Disease linkage
The gene encoding the IκBα protein is mutated in some Hodgkin's lymphoma cells; such mutations inactivate the IκBα protein, thus causing NF-κB to be chronically active in the lymphoma tumor cells and this activity contributes to the malignant state of these tumor cells.[7]
Interactions
IκBα has been shown to interact with:
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000100906 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021025 - Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ Jacobs MD, Harrison SC (1998). "Structure of an IkappaBalpha/NF-kappaB complex". Cell. 95 (6): 749–58. doi:10.1016/S0092-8674(00)81698-0. PMID 9865693. S2CID 7003353.
- ↑ Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S (1995). "Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation". Genes Dev. 9 (22): 2723–35. doi:10.1101/gad.9.22.2723. PMID 7590248.
- ↑ Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT (1999). "Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha". Oncogene. 18 (20): 3063–70. doi:10.1038/sj.onc.1202893. PMID 10340377. S2CID 8269256.
- ↑ Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K (January 2000). "Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination". J. Biol. Chem. 275 (4): 2877–84. doi:10.1074/jbc.275.4.2877. PMID 10644755.
- 1 2 Spencer E, Jiang J, Chen ZJ (February 1999). "Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP". Genes Dev. 13 (3): 284–94. doi:10.1101/gad.13.3.284. PMC 316434. PMID 9990853.
- ↑ "Molecular Interaction Database". Archived from the original on 2006-05-06. Retrieved 2012-05-08.
- 1 2 3 Cohen L, Henzel WJ, Baeuerle PA (September 1998). "IKAP is a scaffold protein of the IkappaB kinase complex". Nature. 395 (6699): 292–6. Bibcode:1998Natur.395..292C. doi:10.1038/26254. PMID 9751059. S2CID 4327300.
- 1 2 Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV (October 1997). "IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK". Science. 278 (5339): 866–9. Bibcode:1997Sci...278..866W. doi:10.1126/science.278.5339.866. PMID 9346485.
- ↑ DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (August 1997). "A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB". Nature. 388 (6642): 548–54. doi:10.1038/41493. PMID 9252186. S2CID 4354442.
- ↑ Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (March 1999). "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature. 398 (6724): 252–6. Bibcode:1999Natur.398..252N. doi:10.1038/18465. PMID 10094049. S2CID 4421236.
- ↑ Crépieux P, Kwon H, Leclerc N, Spencer W, Richard S, Lin R, Hiscott J (December 1997). "I kappaB alpha physically interacts with a cytoskeleton-associated protein through its signal response domain". Mol. Cell. Biol. 17 (12): 7375–85. doi:10.1128/MCB.17.12.7375. PMC 232593. PMID 9372968.
- ↑ Prigent M, Barlat I, Langen H, Dargemont C (November 2000). "IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2". J. Biol. Chem. 275 (46): 36441–9. doi:10.1074/jbc.M004751200. PMID 10969074.
- 1 2 3 Hay DC, Kemp GD, Dargemont C, Hay RT (May 2001). "Interaction between hnRNPA1 and IkappaBalpha is required for maximal activation of NF-kappaB-dependent transcription". Mol. Cell. Biol. 21 (10): 3482–90. doi:10.1128/MCB.21.10.3482-3490.2001. PMC 100270. PMID 11313474.
- ↑ Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM (February 1999). "IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex". Mol. Cell. Biol. 19 (2): 1526–38. doi:10.1128/mcb.19.2.1526. PMC 116081. PMID 9891086.
- 1 2 Malek S, Huxford T, Ghosh G (September 1998). "Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB". J. Biol. Chem. 273 (39): 25427–35. doi:10.1074/jbc.273.39.25427. PMID 9738011.
- ↑ Chang NS (March 2002). "The non-ankyrin C terminus of Ikappa Balpha physically interacts with p53 in vivo and dissociates in response to apoptotic stress, hypoxia, DNA damage, and transforming growth factor-beta 1-mediated growth suppression". J. Biol. Chem. 277 (12): 10323–31. doi:10.1074/jbc.M106607200. PMID 11799106.
- ↑ Fischle W, Verdin E, Greene WC (August 2001). "Duration of nuclear NF-kappaB action regulated by reversible acetylation". Science. 293 (5535): 1653–7. Bibcode:2001Sci...293.1653C. doi:10.1126/science.1062374. hdl:11858/00-001M-0000-002C-9FF1-A. PMID 11533489. S2CID 45796404.
- ↑ Kiernan R, Brès V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M (January 2003). "Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65". J. Biol. Chem. 278 (4): 2758–66. doi:10.1074/jbc.M209572200. PMID 12419806.
- ↑ Hansen SK, Baeuerle PA, Blasi F (April 1994). "Purification, reconstitution, and I kappa B association of the c-Rel-p65 (RelA) complex, a strong activator of transcription". Mol. Cell. Biol. 14 (4): 2593–603. doi:10.1128/mcb.14.4.2593. PMC 358627. PMID 8139561.
- ↑ Schouten GJ, Vertegaal AC, Whiteside ST, Israël A, Toebes M, Dorsman JC, van der Eb AJ, Zantema A (June 1997). "IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase". EMBO J. 16 (11): 3133–44. doi:10.1093/emboj/16.11.3133. PMC 1169932. PMID 9214631.
- ↑ Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY (August 2004). "A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes". Nat. Genet. 36 (8): 837–41. doi:10.1038/ng1391. PMID 15247916. S2CID 41123857.
- ↑ Dai RM, Chen E, Longo DL, Gorbea CM, Li CC (February 1998). "Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha". J. Biol. Chem. 273 (6): 3562–73. doi:10.1074/jbc.273.6.3562. PMID 9452483.
Further reading
- Roulston A, Lin R, Beauparlant P, Wainberg MA, Hiscott J (1995). "Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors". Microbiol. Rev. 59 (3): 481–505. doi:10.1128/MMBR.59.3.481-505.1995. PMC 239370. PMID 7565415.
- Hay RT, Vuillard L, Desterro JM, Rodriguez MS (2000). "Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha". Philos. Trans. R. Soc. Lond. B Biol. Sci. 354 (1389): 1601–9. doi:10.1098/rstb.1999.0504. PMC 1692667. PMID 10582246.
- Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, Rao RG, Weiner DB (2004). "HIV-1 Vpr and anti-inflammatory activity". DNA Cell Biol. 23 (4): 239–47. doi:10.1089/104454904773819824. PMID 15142381.
- Caraglia M, Marra M, Pelaia G, Maselli R, Caputi M, Marsico SA, Abbruzzese A (2005). "Alpha-interferon and its effects on signal transduction pathways". J. Cell. Physiol. 202 (2): 323–35. doi:10.1002/jcp.20137. PMID 15389589.
- Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle". Retrovirology. 2 (1): 11. doi:10.1186/1742-4690-2-11. PMC 554975. PMID 15725353.
- Zhao RY, Bukrinsky M, Elder RT (2005). "HIV-1 viral protein R (Vpr) & host cellular responses". Indian J. Med. Res. 121 (4): 270–86. PMID 15817944.
- Sun XF, Zhang H (2007). "NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases". Histol. Histopathol. 22 (12): 1387–98. PMID 17701919.
External links
- OMIM entries on Ectodermal Dysplasia, Anhidrotic, with T-cell Immunodeficiency
- NFKBIA+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- NF-kappaB+inhibitor+alpha at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P25963 (NF-kappa-B inhibitor alpha) at the PDBe-KB.
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