tailieunhanh - Báo cáo khoa học: TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase–AKT–JNK pathway

Interleukin-1 (IL-1) induces multiple genes via activation of transcription factors that include NF-jB and activator protein-1 (AP-1).We found that IL-1-mediated c-Src acti-vation was required for AP-1 activation, but not for NF-jB activation and also revealed that c-Src-induced AP-1 acti-vation was enhanced synergistically by the coexpression of TNF receptor associated factor 6 (TRAF6).In addition, c-Src interacts with TRAF6 in response to IL-1 and this interaction is required for c-Src activity | Eur. J. Biochem. 270 1257-1268 2003 FEBS 2003 doi TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway Megumi Funakoshi-Tago1 Kenji Tago2 Yoshiko Sonoda1 Shin-ichi Tominaga2 and Tadashi Kasahara1 1Department of Biochemistry Kyoritsu College of Pharmacy 1-5-30 Shibakoen Minato-ku Tokyo 105-8512 Japan department of Biochemistry Jichi Medical School 3311-1 Minamikawachi-machi Tochigi-ken 329-0433 Japan Interleukin-1 IL-1 induces multiple genes via activation of transcription factors that include NF-kB and activator protein-1 AP-1 . We found that IL4-mediated c-Src acii-vation was required for AP-1 activation but not for NF-kB activation and also revealed that c-Src-induced AP-1 activation was enhanced synergistically by the coexpression of TNF receptor associated factor 6 TRAF6 . hl iiddilion. c-Src interacts with TRAF6 in response to IL-1 and this interaction is required for c-Src activity. However neither dominant negative mutants of TRAF6 TRAF6 DN nor kinase-dead mutant of c-Src c-Src KD counteracted each-induced AP-1 activation suggesting no hierarchy between these two molecules. During the TRAF6 and c-Scc-induced AP-1 activation phosphatidylinositol 3 PI3 -kinase its downstream signaling molecule Akt and c-Jun N-tetminal kinase JNK were significantly activated and inhibition of these kinase activities down-regulated AP-1 activation through the suppression of c-fos expression. Furthermore. TRAF6 and c-Src-indurtd JNK activation was significantly inhibited by PI3-kinase inhibitor or a dominant negative mutant of Akt Akt DN . Talton togeflier uur reuuSts demonstrate that c-Src and TRAF6 are key mediators of IL-1-induced AP-1 activation and provide evidence of cross talk between c-Src and TRAF6 molecules through PI3 kinase-Akt-JNK pathways. Keywords NF-kB activation activator protein-1 AP-1 Src kinase TRAF6 c-Jun N-terminal kinase JNK . Interleukin-1 IL-1 is a potent activator of immune and inflammatory .