The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL.
The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL.
复制标题
嵌合泛素连接酶 SH2-U-box 通过靶向天然和 T315I 突变体 BCR-ABL 抑制伊马替尼敏感和耐药 CML 的生长
DOI：
10.1038/srep28352
复制
发表时间：
2016-06-22
影响因子：
4.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Ru Y;Wang Q;Liu X;Zhang M;Zhong D;Ye M;Li Y;Han H;Yao L;Li X
慢性粒细胞白血病（CML）以组成型激活的融合蛋白酪氨酸激酶BCR-ABL为特征，尽管BCR-ABL的酪氨酸激酶抑制剂伊马替尼（TKI）是CML的一线治疗药物，但获得性耐药几乎不可避免。其潜在机制是BCR-ABL基因内的点突变，其中T315 I是臭名昭著的，因为它抵抗几乎所有目前可用的抑制剂。在这里，我们利用先前产生的嵌合泛素连接酶SH 2-U-box，其中来自衔接蛋白Grb 2的SH 2充当活化的BCR-ABL的结合结构域，而来自CHIP的U-box充当E3泛素连接酶结构域，以便靶向天然和T315 I突变的BCR-ABL的泛素化和降解。在携带野生型或T315 I突变型BCR-ABL（K562或K562 R）的CML细胞中，SH 2-U-box显著抑制增殖并诱导凋亡，BCR-ABL依赖性信号通路被抑制。此外，SH 2-U-box在K562细胞中与伊马替尼协同工作。重要的是，携带SH 2-U-box的慢病毒可以显著抑制裸鼠中K562异种移植物或SCID小鼠中K562 R异种移植物以及原代CML细胞的生长。总的来说，通过降解天然和T315 I突变的BCR-ABL，嵌合泛素连接酶SH 2-U-box可以作为伊马替尼敏感和耐药CML的潜在治疗方法。
Chronic myeloid leukemia (CML) is characterized by constitutively active fusion protein tyrosine kinase BCR-ABL. Although the tyrosine kinase inhibitor (TKI) against BCR-ABL, imatinib, is the first-line therapy for CML, acquired resistance almost inevitably emerges. The underlying mechanism are point mutations within theBCR-ABLgene, among which T315I is notorious because it resists to almost all currently available inhibitors. Here we took use of a previously generated chimeric ubiquitin ligase, SH2-U-box, in which SH2 from the adaptor protein Grb2 acts as a binding domain for activated BCR-ABL, while U-box from CHIP functions as an E3 ubiquitin ligase domain, so as to target the ubiquitination and degradation of both native and T315I-mutant BCR-ABL. As such, SH2-U-box significantly inhibited proliferation and induced apoptosis in CML cells harboring either the wild-type or T315I-mutant BCR-ABL (K562 or K562R), with BCR-ABL-dependent signaling pathways being repressed. Moreover, SH2-U-box worked in concert with imatinib in K562 cells. Importantly, SH2-U-box-carrying lentivirus could markedly suppress the growth of K562-xenografts in nude mice or K562R-xenografts in SCID mice, as well as that of primary CML cells. Collectively, by degrading the native and T315I-mutant BCR-ABL, the chimeric ubiquitin ligase SH2-U-box may serve as a potential therapy for both imatinib-sensitive and resistant CML.
DOI：
10.3760/cma.j.issn.0253-2727.2015.07.005
发表时间：
2015-07
影响因子：
--
作者：
Bao X;Qiu H;Chen S;Ma X;Tang X;Fu C;Sun A;Wu D
通讯作者：
Wu D