TAILIEUCHUNG - Báo cáo khoa học: Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase

We report the development of a high-level bacterial expression system for the Alzheimer’s disease-associated amyloid b-peptide (Ab), together with a scaleable and inexpensive purification procedure. Ab(1–40) and Ab(1–42) coding sequences together with added ATG codons were cloned directly into a Pet vector to facilitate production of Met-Ab(1–40) and Met-Ab(1– 42), referred to as Ab(L1–40) and Ab(L1–42), respectively. | Mitogen-activated protein kinase phosphatase-1 modulated JNK activation is critical for apoptosis induced by inhibitor of epidermal growth factor receptor-tyrosine kinase Kenji Takeuchi1 Tomohiro Shin-ya1 Kazuto Nishio2 and Fumiaki Ito1 1 Department of Biochemistry Faculty of PharmaceuticalSciences Setsunan University Osaka Japan 2 Department of Genome Biology Kinki University Schoolof Medicine Osaka Japan Keywords AG1478 c-Jun N-terminalkinase epidermal growth factor receptor mitogen-activated protein kinase phosphatase-1 non-small-cell lung cancer Correspondence K. Takeuchi Department of Biochemistry Faculty of Pharmaceutical Sciences Setsunan University Hirakata Osaka 5730101 Japan Fax 81 72 866 3117 Tel 81 72 866 3118 E-mail takeuchi@ Received 29 August 2008 revised 6 December 2008 accepted 16 December 2008 doi Alterations resulting in enhanced epidermal growth factor receptor EGFR expression or function have been documented in a variety of tumors. Therefore EGFR-tyrosine kinase is a promising therapeutic target. Although in vitro and in vivo studies have shown the anti-tumor activity of EGFR-tyrosine kinase inhibitors against various tumor types little is known about the mechanism by which such inhibitors effect their antitumor action. AG1478 is known to selectively inhibit EGFR-tyrosine kinase. In this study we showed that AG1478 caused apoptosis and apoptosis-related reactions such as the activation of caspase 3 in human nonsmall cell lung cancer cell line PC-9. To investigate the signaling route by which AG1478 induced apoptosis we examined the activation of c-Jun N-terminal kinase JNK and mitogen-activated protein kinase p38 in AG1478-treated PC-9 cells. JNK but not p38 was significantly activated by AG1478 as determined by both immunoblot analysis for levels of phosphorylated JNK and an in vitro activity assay. Various types of stimuli activated JNK through phosphorylation by the dual-specificity JNK .

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