Activation of the JNK pathway promotes phosphorylation and degradation of Bim(EL) - a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia
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摘要T-cell acute lymphoblastic leukemias (T-ALLs) are highly malignant tumors with 20% of patients continues to fail therapy, in part due to chemoresistance of T-ALL cells via largely unknown mechanisms. Here, we showed that lack of Bcl-2-interacting mediator of cell death (Bim)(EL) protein expression, a BH3-only member of the Bcl-2 family proteins, conferred resistance of a T-ALL cell line, Sup-T1, to etoposide-induced apoptosis. Overexpression of Bim(EL) significantly restored its sensitivity to etoposide-induced caspase activation and poly(ADP-ribose) polymerase cleavage. Surprisingly, we found that constitutive activation of the c-Jun N-terminal kinase (JNK) pathway in Sup-T1 cells promoted phosphorylation and degradation of Bim(EL) via the proteosome. Blocking with a proteosome inhibitor yielded an elevated level of Bim(EL) and accumulation of Bim(EL) species phosphorylated at Ser(69). Pretreatment of Sup-T1 cells with a specific JNK inhibitor, SP600125, also increased the Bim(EL) level and resensitized the cells to etoposide-induced apoptosis. Together, our findings suggest that the JNK activation status may correlate with the Bim(EL) level and in turn can control the sensitivity of T-ALL cells to chemotherapeutic agents.
著者Leung KT, Li KKH, Sun SSM, Chan PKS, Ooi VEC, Chiu LCM
期刊名稱Carcinogenesis
出版年份2008
月份3
日期1
卷號29
期次3
出版社OXFORD UNIV PRESS
頁次544 - 551
國際標準期刊號0143-3334
電子國際標準期刊號1460-2180
語言英式英語
Web of Science 學科類別Oncology; ONCOLOGY

上次更新時間 2020-20-05 於 02:39