Dissertation > Excellent graduate degree dissertation topics show

Heat Shock Protein 90 (Hsp90) Regulates the Stability of TAK1 in IL-1β-induced Cell Signaling

Author: ShiLiJun
Tutor: YinZhiMin
School: Nanjing Normal University
Course: Biochemistry and Molecular Biology
Keywords: Heat shock protein 90 Transforming growth factor - beta - activated kinase 1 Geldanamycin Interleukin -1β Inflammation Signal Transduction
CLC: R341
Type: Master's thesis
Year: 2008
Downloads: 248
Quote: 1
Read: Download Dissertation

Abstract

Heat shock protein 90 (Heat shock protein 90, Hsp90) is a member of the Hsp90 family, highly conserved in evolution, its structure is mainly composed of highly conserved N-terminal ATPase domain, a middle domain and a mediated dimerization of Hsp90 C terminal domain is composed of three parts. Hsp90 is the widespread presence of a molecular chaperone in the intracellular, its substrate proteins play an important role in the intracellular signaling pathways, steroid hormone receptor, protein kinases, transcription factors, etc.. Hsp90 specific inhibitors of GA or RAD, blocking its chaperone function by competitive binding to the the Hsp90 N end of the ATP / ADP binding site, resulting in its substrate protein degradation by the proteasome. Thus, by means of Hsp90 inhibitors can further expand the substrate range of the Hsp90. IL-1 is a pro-inflammatory cytokine, generated mainly by LPS-stimulated monocytes / macrophages, and has an important role in the immune response and immune deficiency diseases such as rheumatoid arthritis (rheumatoid arthritis, RA). TAK1 as a MAPKKK involved in signaling pathways induced by IL-1β, and downstream MAPKs (JNK and p38) and the activation of NF-κ3 is required. The proteomics studies show Hsp90 interaction with TAK1. Our study found that reported Hsp90 in signaling cascades activated by IL-1β in the new role. GA treatment inhibited IL-1β-induced, TAK1-MAPKs and TAK1-NF-κ3 pathway activation, resulting in the reduction of inflammation-related protein expression of COX-2. Means of RNA interference down endogenous Hsp90 protein levels, we get the same result. In addition, T6RZC stably expressing cell lines can be provided through the Coumermycin A the induction T6RZC dimerization, so that the analog IL-1β-activated intracellular signal cascade, to avoid the Hsp90 chaperone complex TAK1 upstream kinases IRAK-1 regulation of MAPKs and NF-κB activation. GA significantly inhibited JNK, p38 of MAPKs phosphorylation and IκB degradation in T6RZC stably expressing cell lines. Immunoprecipitation assay results show that Hsp90 able to interact in vivo with TAK1 and the 1-401 amino acid of the amino group of HSP90 client mediated by a combination of both. Hsp90 inhibitors can cut endogenous TAK1 expression at the posttranscriptional level without affecting the level of its mRNA, and the GA-treated the TAK1 protein degradation through the proteasome pathway. These results suggest that Hsp90 protein interactions occurred with TAK1 to regulate IL-1β activation of MAPKs and NF-κB signaling transduction pathway. In summary, this study is the first to reveal the Hsp90 stability by regulating TAK1 protein involved in signaling cascades activated by IL-1β; proposed new mechanism of action of Hsp90 intracellular regulation of MAPKs and NF-κB pathway. These results have important guiding significance for the in-depth study of the role of Hsp90 in the regulation of inflammation-related signaling pathways.

Heat Shock Protein 90 (Hsp90) Regulates the Stability of TAK1 in IL-1β-induced Cell Signaling

Abstract

Related Dissertations