Abstract |
The ubiquitin ligase Cbl-b is a negative regulator of the PI3K/Akt pathway, the survival pathway implicated in chemotherapy resistance. However, it remains unclear whether Cbl-b can regulate chemosensitivity through modulating Akt activation. In this study, VP-16-induced RBL-2H3 cells apoptosis was accompanied by the activation of Akt and ERK. The PI3K inhibitor LY294002, not the ERK inhibitor PD98059, enhanced the apoptosis. In addition, down-regulation of Cbl-b was also detected. Over expression of Cbl-b significantly enhanced VP-16-induced cell apoptosis with inhibition of Akt activity, while a dominant negative (DN) RING Finger domain mutation completely abolished this enhancement. On the other hand, ERK activity was enhanced by Cbl-b, and the ERK inhibitor PD98059 reversed Cbl-b-enhanced apoptosis. The consistent results were also showed in the process of Ara-c treatment. These observations indicate that Cbl-b promotes RBL-2H3 apoptosis induced by VP-16 or Ara-c, probably through inhibition of Akt and activation of ERK.
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Authors | Xiujuan Qu, Yingchun Li, Jing Liu, Ling Xu, Ye Zhang, Xuejun Hu, Kezuo Hou, Yunpeng Liu |
Journal | Molecular and cellular biochemistry
(Mol Cell Biochem)
Vol. 340
Issue 1-2
Pg. 107-14
(Jul 2010)
ISSN: 1573-4919 [Electronic] Netherlands |
PMID | 20177738
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Antimetabolites, Antineoplastic
- Antineoplastic Agents, Phytogenic
- Cblb protein, rat
- Enzyme Inhibitors
- Phosphoinositide-3 Kinase Inhibitors
- Cytarabine
- Etoposide
- Proto-Oncogene Proteins c-cbl
- Proto-Oncogene Proteins c-akt
- Extracellular Signal-Regulated MAP Kinases
- Mitogen-Activated Protein Kinase Kinases
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Topics |
- Adaptor Proteins, Signal Transducing
(genetics, metabolism)
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Cell Survival
- Cytarabine
(pharmacology)
- Dose-Response Relationship, Drug
- Enzyme Activation
- Enzyme Inhibitors
(pharmacology)
- Etoposide
(pharmacology)
- Extracellular Signal-Regulated MAP Kinases
(antagonists & inhibitors, metabolism)
- Inhibitory Concentration 50
- Leukemia, Basophilic, Acute
(enzymology, genetics, pathology)
- Mitogen-Activated Protein Kinase Kinases
(metabolism)
- Mutation
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Proto-Oncogene Proteins c-akt
(metabolism)
- Proto-Oncogene Proteins c-cbl
(genetics, metabolism)
- Rats
- Time Factors
- Transfection
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