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http://dx.doi.org/10.5352/JLS.2016.26.9.991

Hsp70 and IKKγ Synergistically Suppress the Activation of NF-κB  

Kim, Mi Jeong (Department of BioHealth Sciences, Changwon National University)
Kim, Ka Hye (Department of BioHealth Sciences, Changwon National University)
Kim, Moon Jeong (Department of BioHealth Sciences, Changwon National University)
Kim, Jin Ik (Department of BioHealth Sciences, Changwon National University)
Choi, Hye Jung (Department of Biology and Chemistry, Changwon National University)
Moon, Ja Young (Department of BioHealth Sciences, Changwon National University)
Joo, Woo Hong (Department of Biology and Chemistry, Changwon National University)
Kim, Dong Wan (Department of BioHealth Sciences, Changwon National University)
Publication Information
Journal of Life Science / v.26, no.9, 2016 , pp. 991-998 More about this Journal
Abstract
NF-κB acts as a critical transcription factor for the survival of cells via the induction of antiapoptotic genes. Constitutive activation of NF-κB in many types of solid tumors suggests that the inhibition of NF-κB might prevent or inhibit tumorigenesis. Although a number of studies demonstrated that Hsp70 regulated NF-κB activity, the exact mechanism is not clear. This study investigated the functional relationship of Hsp70 and IKKγ in the regulation of NF-κB activation using expression plasmids of components of the IKK complex. Wild-type and deletion mutants of IKKγ were expressed together with Hsp70, and the combined regulatory effect of Hsp70 and IKKγ on NF-κB activation was assayed. Hsp70 suppressed the activation of NF-κB in a reporter plasmid assay. Hsp70 also suppressed the phosphorylation and degradation of IκBα. The suppressive effect of Hsp70 on NF-κB activation was synergistically elevated by IKKγ. The N-terminal IKKβ binding site, C-terminal leucine zipper, and zinc finger domains of IKKγ were not necessary for the suppressive effect. Furthermore, Hsp70 and IKKγ synergistically suppressed the induction of COX-2 expression by lipopolysaccharides in RAW264.7 cells. These results suggest that overexpression of Hsp70 and IKKγ may be a strategic method for inhibition of NF-κB and related diseases.
Keywords
COX-2; Hsp70; IKKcomplex; IKKγ ; NF-κ B;
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1 Amde, S., Joshua, M. and Marshall, S. 2008. IKKγ (NEMO) is involved in the coordination of the AP-1 and NF-κB pathways. Mol. Cell. Biochem. 310, 181-190.   DOI
2 Asea, A., Kraeft, S. K., Kurt-Jones, E. A., Stevenson, M. A., Chen, L. B., Finberg, R. W., Koo, G. C. and Calderwood, S. K. 2000. Hsp70 stimulates cytokine production through a CD 14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6, 435-442.   DOI
3 Blachere, N. E., Li, Z., Chandawarkar, R. Y., Suto, R., Jaikaria, N. S., Basu, S., Udono, H. and Srivastava, P. K. 1997. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186, 1315-1322.   DOI
4 DiDonato, J. A., Mercurio, F. and Karin, M. 2012. NF-κB and the link between inflammation and cancer. Immunol. Rev. 246, 379-400.   DOI
5 Cao, W., Li, M., Li, J., Li, C., Xu, X. and Gu, W. 2015. Geranylgeranylacetone ameliorate lung ischemia/reperfusion injury by Hsp70 and thioredoxin redox system : NF-κB pathway involved. Pulm. Pharmacol. Ther. 32, 109-115.   DOI
6 Chariot, A. 2009. The NF-κB-independent functions of IKK subunits in immunity and cancer. Trends Cell Biol. 19, 404-413.   DOI
7 Criollo, A., Senonilla, L. and Authier, H. 2010. The IKK complex contributes to the induction of autophagy. EMBO J. 29, 619-631.   DOI
8 Ghosh, G., Wang, V. Y., Huang, D. B. and Fusco, A. 2012. NF-κB regulation: lessons from structures. Immunol. Rev. 246, 36-38.   DOI
9 Ghosh, S. and Febin Prabhu Dass, J. 2016. Non-canonical pathway network modelling and ubiquitination site prediction through homology modelling of NF-kB. Gene 581, 48-56.   DOI
10 Hayden, M. S. and Ghosh, S. 2008. Shared principles in NF-κB signaling. Cell 132, 344-362.   DOI
11 Hinz, M., Arslan, S. C. and Scheidereit, C. 2012. It takes two to tango: IκBs, the multifunctional partners of NF-κB. Immunol. Rev. 246, 59-66.   DOI
12 Kalmar, B., Lu, C. H. and Greensmith, L. 2014. The role of heat shock proteins in Amylotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol. Pharmacol. Ther. 141, 40-54.   DOI
13 Kretz-Remy, C., Munseh, B. and Arrigo, A. P. 2001. NF-κB-dependent transcriptional activation during heat shock recovery: thermolability of the NF-κB·IκB complex. J. Biol. Chem. 276, 43723-43733.   DOI
14 Li, X. H., Fang, X. and Gaynor, R. B. 2001. Role of Ikkγ/NEMO in assembly of the ikappa B kinase complex. J. Biol. Chem. 276, 4494-4500.   DOI
15 Kwon, W. J., Kim, S. H., Park, Y. O., Cho, M., Kang, C. D., Lee, G., An, W. G., Joo, W. H. and Kim, D. W. 2004. IKKγ inhibits activation of NF-κB by NIK. Mol. Cells 18, 200-206.
16 Lawrence, T. and Fong, C. 2010. The resolution of inflammation: anti-inflammatory roles for NF-κB. Int. J. Biochem. Cell Biol. 42, 519-523.   DOI
17 Li, S., Ma, X., Ma, L., Wang, C., He, Y. and Yu, Z. 2013. Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells. J. Exp. Clin. Cancer Res. 32, 11-17   DOI
18 Mauro, C., Pacifico, F., Lavorgna, A., Mellone, S., Iannetti, A., Acquaviva, R., Formisano, S., Vito, P. and Leonardi, A. 2006. ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB. J. Biol. Chem. 281, 18482-18488.   DOI
19 Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J., Young, D. B. and Rao, A. 1997. Ikk-1 and Ikk-2: Cytokine-activated ikappa B kinase essential for NF-kB activation. Science 278, 860-866.   DOI
20 Morgan, M. J. and Liu, Z. G. 2011. Crosstalk of reactive oxigen species and NF-κB signaling. Cell Res. 21, 103-115.   DOI
21 Nivon, M., Richet, E., Codogno, P., Ariigo, A. P. and Kretz-Remy, C. 2009. Autophagy activation by NF-κB is essential for cell survival after heat shock. Autophagy 5, 766-783.   DOI
22 Oeckinghaus, A., Hayden, M. S. and Ghosh, S. 2011. Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12, 695-708.
23 Regula, K. M., Ens, K. and Kirshenbaum, L. A. 2002. IKKβ is required for Bcl-2-mediated NF-κB activation in ventricular myocytes. J. Biol. Chem. 277, 38676-38682.   DOI
24 Prashanth, A. K. and Levine, A. J. 2010. p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism. FASEB J. 24, 3643-3652.   DOI
25 Quaglio, A. E., Castilho, A. C. and Di Stasi, L. C. 2015. Experimental evidence of heparanase, Hsp70 and NF-kB gene expression on the response of anti-inflammatory drugs in TNBS-induced colonic inflammation. Life Sci. 141, 179-187.   DOI
26 Rapino, F., Abhari, B. A., Jung, M. and Fulda, S. 2015. NIK is required for NF-kB-mediated induction of BAG3 upon inhibition of constitutive protein degradation pathway. Cell Death Dis. 6, e1692.   DOI
27 Repalli, J. and Meruelo, D. 2015. Screening strategies to identify Hsp70 modulators to treat Alzheimer’s disease. Drug. Des. Devel. Ther. 9, 321-331.
28 Ritossa, F. A. 1962. A new puffing pattern induced by temperature shock and DNP in Drosophillia. Experientia 18, 571-573.   DOI
29 Srivastava, P. 2002. Roles of heat-shock proteins in innate and adaptive immunity. Nat. Rev. Immunol. 2, 185-194.   DOI
30 Smale, S. T. 2011. Hierarchies of NF-κB target-gene regulation. Nat. Immunol. 12, 689-694.
31 Udono, H. and Srivastava, P. K. 1993. Heat shock protein 70-associated peptides elicit specific cancer immunity. J. Exp. Med. 178, 1391-1396.   DOI
32 Vasudevan, K. M., Gurumurthy, S. and Rangnekar, V. M. 2004. Suppression of PTEN expression by NF-κB prevents apoptosis. Mol. Cell. Biol. 24, 1007-1021.   DOI
33 Zhan, P., Qian, Q. and Yu, L. 2013. Prognostic value of COX-2 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis. J. Thorac. Dis. 40-47.
34 Yamada, H., Kikuchi, S., Inui, T., Takahashi, H. and Kimura, K. 2014. Gentiolactone, a secoiridoid dilactone from Gentiana trifola, inhibits TNF-α, iNOS and Cox-2 mRNA expression and blocks NF-kB promoter activity in murine macrophages. PLoS One 9, e113834.   DOI
35 Yamamoto, Y., Kim, D. W., Kwak, Y. T., Parajapati, S., Verma, U. and Gaynor, R. B. 2001. IKKγ/NEMO facilitates the recruitment of the IκB proteins into the IκB kinase complex. J. Biol. Chem. 276, 36327-36336.   DOI
36 Zha, L., Chen, J., Sun, S., Mao, L., Chu, X., Deng, H., Cai, J., Li, X., Liu, Z. and Cao, W. 2014. Soyasaponins can blunt inflammation by inhibiting the reactive oxygen species-mediated activation of PI3K/Akt/NF-kB pathway. PLoS One 9, e107655.   DOI