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We investigated the survival signals of epidermal growth factor (EGF) in human gastric adenocarcinoma cell line TMK-1. Treatment of TMK-1 cells with adriamycin (ADR) caused apoptosis and apoptosis-related reactions such as the release of cytochromecfrom mitochondria and the activation of caspase 9. | ỊFEBS Journal Role of transcription factor activator protein 1 API in epidermal growth factor-mediated protection against apoptosis induced by a DNA-damaging agent Kenji Takeuchi Yu-ichiro Motoda and Fumiaki Ito Department of Biochemistry Faculty of PharmaceuticalSciences Setsunan University Osaka Japan Keywords activator protein 1 AP1 adriamycin Bcl-XL epidermalgrowth factor MAP kinase Correspondence K. Takeuchi Department of Biochemistry Faculty of Pharmaceutical Sciences Setsunan University Hirakata Osaka 573-0101 Japan Fax 81 72 866 3117 Tel. 81 72 866 3118 E-mail takeuchi@pharm.setsunan.ac.jp Received 31 March 2006 revised 3 June 2006 accepted 14 June 2006 doi 10.1111 j.1742-4658.2006.05377.x We investigated the survival signals of epidermal growth factor EGF in human gastric adenocarcinoma cell line TMK-1. Treatment of TMK-1 cells with adriamycin ADR caused apoptosis and apoptosis-related reactions such as the release of cytochrome c from mitochondria and the activation of caspase 9. However EGF treatment greatly reduced the ADR-induced apoptosis as well as these reactions. We previously reported that hepatocyte growth factor transmitted protective signals against ADR-induced apoptosis by causing activation of the phosphatidylinositol-3 -OH kinase PtdIns3-K Akt signaling pathway in human epithelial cell line MKN74 Takeuchi K Ito F 2004 J Biol Chem 279 892-900 . However PtdIns3-K Akt signaling did not mediate the antiapoptotic action of EGF in TMK-1 cells. EGF increased the expression of the Bcl-XL protein an antiapoptotic member of the Bcl-2 family but not that of other anti Bcl-2 or proapoptotic Bad and Bax protein members. Expression of the c-Fos and c-Jun components of activator protein 1 API which are known to regulate bcl-XL gene transcription were increased in response to EGF. Pretreatment of the cells with PD98059 an inhibitor of MAP kinase kinase inhibited the EGF-induced c-Fos and c-Jun expression AP1 DNA binding Bcl-XL expression and the resistance
