Role of transcription factor activator protein 1 (AP1) in epidermal growth factor‐mediated protection against apoptosis induced by a DNA‐damaging agent

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Abstract
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 Chem279, 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 (AP1), 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 against ADR‐induced apoptosis, suggesting that EGF transmitted the antiapoptotic signal in such a way that it activated AP1 via a MAP kinase signaling pathway. TMK‐1 cells stably transfected with TAM67, c‐Jun dominant‐negative mutant, did not display EGF‐induced Bcl‐XL expression or resistance against ADR‐induced apoptosis. These results indicate that AP1‐mediated upregulation of Bcl‐XL expression is critical for protection of TMK‐1 cells against ADR‐induced apoptosis.