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Activation of the JNK pathway promotes phosphorylation and degradation of BimEL--a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia.
- Source :
-
Carcinogenesis [Carcinogenesis] 2008 Mar; Vol. 29 (3), pp. 544-51. Date of Electronic Publication: 2008 Jan 03. - Publication Year :
- 2008
-
Abstract
- 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.
- Subjects :
- Antineoplastic Agents, Phytogenic pharmacology
Apoptosis drug effects
Bcl-2-Like Protein 11
Blotting, Western
Enzyme Activation
Etoposide pharmacology
Humans
Hydrolysis
Leukemia-Lymphoma, Adult T-Cell enzymology
Leukemia-Lymphoma, Adult T-Cell pathology
Phosphorylation
Reverse Transcriptase Polymerase Chain Reaction
Apoptosis Regulatory Proteins metabolism
Drug Resistance, Neoplasm
Leukemia-Lymphoma, Adult T-Cell metabolism
MAP Kinase Kinase 4 metabolism
Membrane Proteins metabolism
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2180
- Volume :
- 29
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Carcinogenesis
- Publication Type :
- Academic Journal
- Accession number :
- 18174237
- Full Text :
- https://doi.org/10.1093/carcin/bgm294