Activation of the JNK pathway promotes phosphorylation and degradation of BimEL--a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia
| Autor: | Samuel S. M. Sun, Lawrence C.-M. Chiu, Karen Kwai-Har Li, Vincent E.C. Ooi, Kam Tong Leung, Paul K.S. Chan |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Programmed cell death MAP Kinase Kinase 4 T cell Blotting Western Apoptosis hemic and lymphatic diseases Proto-Oncogene Proteins medicine Humans Leukemia-Lymphoma Adult T-Cell Phosphorylation Caspase Etoposide biology Bcl-2-Like Protein 11 Kinase Reverse Transcriptase Polymerase Chain Reaction Hydrolysis Membrane Proteins hemic and immune systems General Medicine Antineoplastic Agents Phytogenic Enzyme Activation medicine.anatomical_structure Proteasome Drug Resistance Neoplasm Mitogen-activated protein kinase Cancer research biology.protein biological phenomena cell phenomena and immunity Apoptosis Regulatory Proteins |
| Zdroj: | Carcinogenesis. 29(3) |
| ISSN: | 1460-2180 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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