論文 - 詳細
| RRC ID | 81462 |
|---|---|
| 著者 | Shibata N, Ohoka N, Tsuji G, Demizu Y, Miyawaza K, Ui-Tei K, Akiyama T, Naito M. |
| タイトル | Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells. |
| ジャーナル | Oncogene |
| Abstract |
Fusion genes resulting from chromosomal rearrangements are frequently found in a variety of cancer cells. Some of these are known to be driver oncogenes, such as BCR-ABL in chronic myelogenous leukemia (CML). The products of such fusion genes are abnormal proteins that are ordinarily degraded in cells by a mechanism known as protein quality control. This suggests that the degradation of BCR-ABL protein is suppressed in CML cells to ensure their proliferative activity. Here, we show that ubiquitin-specific protease 25 (USP25) suppresses the degradation of BCR-ABL protein in cells harboring Philadelphia chromosome (Ph). USP25 was found proximal to BCR-ABL protein in cells. Depletion of USP25 using shRNA-mediated gene silencing increased the ubiquitylated BCR-ABL, and reduced the level of BCR-ABL protein. Accordingly, BCR-ABL-mediated signaling and cell proliferation were suppressed in BCR-ABL-positive leukemia cells by the depletion of USP25. We further found that pharmacological inhibition of USP25 induced rapid degradation of BCR-ABL protein in Ph-positive leukemia cells, regardless of their sensitivity to tyrosine kinase inhibitors. These results indicate that USP25 is a novel target for inducing the degradation of oncogenic BCR-ABL protein in Ph-positive leukemia cells. This could be an effective approach to overcome resistance to kinase inhibitors. |
| 巻・号 | 39(19) |
| ページ | 3867-3878 |
| 公開日 | 2020-5-1 |
| DOI | 10.1038/s41388-020-1253-0 |
| PII | 10.1038/s41388-020-1253-0 |
| PMID | 32203161 |
| MeSH | Cell Proliferation / drug effects Deubiquitinating Enzymes / genetics Drug Resistance, Neoplasm / genetics Gene Silencing / drug effects Genes, abl / genetics* Humans Jurkat Cells K562 Cells Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics* Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology Philadelphia Chromosome* Protein Kinase Inhibitors / pharmacology Proteolysis / drug effects RNA, Small Interfering / genetics Ubiquitin Thiolesterase / genetics* |
| IF | 7.971 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CS-RfA-EG (RDB04391) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |