論文 - 詳細
| RRC ID | 45214 |
|---|---|
| 著者 | Shintani T, Ohara-Waki F, Kitanaka A, Tanaka T, Kubota Y. |
| タイトル | Cbl negatively regulates erythropoietin-induced growth and survival signaling through the proteasomal degradation of Src kinase. |
| ジャーナル | Blood Cells Mol Dis |
| Abstract |
We examined the biological functions of the gene Cbl in erythropoietin (EPO) signaling using Cbl-deficient F-36P human erythroleukemia cells by the introduction of the Cbl siRNA expression vector. Knockdown of Cbl promoted EPO-dependent proliferation and survival of F-36P cells, especially at a low concentration of EPO (0.01U/mL), similar to serum concentrations of EPO in healthy volunteers (0.005-0.04U/mL). We found that Src was degraded mainly by the proteasomal pathway because the proteasome inhibitor MG-132 but not the lysosome inhibitor NH4Cl suppressed the EPO-induced degradation of Src in F-36P cells and that knockdown of Cbl inhibited EPO-induced ubiquitination and degradation of Src in F-36P cells. The experiments using the Src inhibitor PP1 and co-expression experiments further confirmed that Cbl and the kinase activity of Src are required for the EPO-induced ubiquitination of Src. In addition, the co-expression experiments and in vitro kinase assay demonstrated that the EPO-induced tyrosine phosphorylation and ubiquitination of Cbl were dependent on the kinase activity of Src but not Jak2. Thus, Cbl negatively regulates EPO signaling mainly through the proteasome-dependent degradation of Src, and the E3 ligase activity of Cbl and its tyrosine phosphorylation are regulated by Src but not Jak2. |
| 巻・号 | 53(4) |
| ページ | 211-8 |
| 公開日 | 2014-12-1 |
| DOI | 10.1016/j.bcmd.2014.06.005 |
| PII | S1079-9796(14)00066-7 |
| PMID | 25084697 |
| MeSH | Ammonium Chloride / pharmacology Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Cell Survival / drug effects Erythropoietin / metabolism Erythropoietin / pharmacology* Gene Expression Regulation Humans Janus Kinase 2 / genetics Janus Kinase 2 / metabolism Leupeptins / pharmacology Lymphocytes / cytology Lymphocytes / drug effects* Lymphocytes / metabolism Phosphorylation / drug effects Proteasome Endopeptidase Complex / drug effects Proteasome Endopeptidase Complex / metabolism Proteolysis Proto-Oncogene Proteins c-cbl / antagonists & inhibitors Proto-Oncogene Proteins c-cbl / genetics* Proto-Oncogene Proteins c-cbl / metabolism Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors Proto-Oncogene Proteins pp60(c-src) / genetics* Proto-Oncogene Proteins pp60(c-src) / metabolism Pyrazoles / pharmacology Pyrimidines / pharmacology RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Signal Transduction Ubiquitination |
| IF | 2.46 |
| 引用数 | 4 |
| WOS 分野 | HEMATOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | F-36P(RCB0775) |