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dc.description.abstractTumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is critical for the production of inflammatory cytokines in various Toll-like receptor (TLR)-mediated signaling pathways. However, it is poorly understood how TRAF6 regulates TLR3 responses. Here, I demonstrate that GSK3β interacts with TRAF6 and positively regulates the TLR3-mediated signaling. Suppression of GSK3β expression or its kinase activity drastically reduced the production of inflammatory cytokines and the induction of c-Fos by decreasing extracellular signal-regulated kinase (ERK) and p38 phosphorylation. GSK3β physically associated with TRAF6 in a poly I:C-dependent manner. TRAF6 was determined to be a direct E3 ligase for GSK3β and TRAF6-mediated GSK3β ubiquitination was essential for poly I:C-dependent cytokine production by promoting the TRIF-assembled signaling complex.;Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) 는 다양한 Toll-like receptor (TLR) 과 관련된 신호 전달 과정에서 inflammatory cytokine을 생성하는 데에 있어 매우 중요한 adaptor 기능을 하는 것으로 알려져 있다. 그러나 TRAF6가 어떻게 TLR3 반응을 조절하는지에 대해서는 거의 알려진 바가 없다. 이 논문에서 우리는 GSK3β 가 TRAF6와 interaction하며 TLR3 관련 신호 전달 체계를 양성적으로 조절함을 보였다. GSK3β 의 발현이나 kinase 활성을 억제시켰을때, extracelluar signal-regulated kinase (ERK)와 p38의 phosphorylation을 감소시킴으로써 inflammatory cytokine의 생성과 c-Fos induction양을 극적으로 감소시켰다. 또한GSK3β는poly I:C 에 의해 TRAF6와 생리적으로 interaction을 하였다. TRAF6는 GSK3β의직접적인 E3 ubiquitin ligase로 보여지며, TRAF6에 의해 유도된 GSK3β의ubiquitination은 TRIF에 결합하는 신호 전달 complex를 증진시킴으로써 poly I:C에 의한 cytokine 생성에 필수적으로 작용하고 있다.-
dc.description.tableofcontentsINTRODUCTION 1 MATERIALS AND METHODS 7 Cell culture and transfection 7 Reagents and antibodies 8 Plasmid constructs 9 Immunoprecipitation (IP) and Western blot analysis 9 Enzyme-linked immunosorbent assay (ELISA) 10 Real-time PCR analysis 10 siRNA transfection 13 GST pull-down assay 14 Native PAGE assay 14 Mapping of ubiquitination sites on GSK3β 14 Statistical analysis 15 RESULTS 16 GSK3β positively regulates TLR3-mediated inflammatory cytokine production and type I IFN-β induction 16 GSK3β regulates TLR3-mediated ERK and p38 activation 27 GSK3β regulates expression of c-Fos through ERK and p38 in TLR3 signaling 31 GSK3β is required for the recruitment of TRAF6-TAK1-TAB1-TAB2 complex to TLR3 36 GSK3β interacts with TRAF6 and TAK1 39 TRAF6-mediated GSK3β ubiquitination at lysine 183 is essential for TLR3 signaling 45 Ubiquitination of GSK3β is required for interaction with TRAF6 58 GSK3β is required for TRAF6 phosphorylation in TLR3 signaling 62 GSK3β is required for BTK activation in TLR3 signaling 64 DISCUSSION 67 REFERENCES 74 국문초록 85-
dc.format.extent6850559 bytes-
dc.publisher이화여자대학교 대학원-
dc.titleThe functional study of GSK3β in TLR3 signaling-
dc.typeDoctoral Thesis-
dc.creator.othernameKo, Ryeo jin-
dc.format.pagevi ,85 p.-
dc.identifier.major대학원 생명과학과- 2-
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