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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AbstractT-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.
All Author(s) ListLeung KT, Li KKH, Sun SSM, Chan PKS, Ooi VEC, Chiu LCM
Journal nameCarcinogenesis
Year2008
Month3
Day1
Volume Number29
Issue Number3
PublisherOXFORD UNIV PRESS
Pages544 - 551
ISSN0143-3334
eISSN1460-2180
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesOncology; ONCOLOGY

Last updated on 2020-23-03 at 03:46