Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation
Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation
复制标题
Cbl-b通过抑制PI3K/Akt激活和增强MEK/ERK激活促进化疗诱导的大鼠嗜碱性白血病细胞凋亡
DOI：
10.1007/s11010-010-0407-8
复制
发表时间：
2010-07-01
影响因子：
4.3
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
--
作者：
Qu, Xiujuan;Li, Yingchun;Liu, Yunpeng
泛素连接酶 Cbl-b 是 PI3K/Akt 通路的负调节因子，该通路与化疗耐药有关。然而，目前尚不清楚 Cbl-b 是否可以通过调节 Akt 激活来调节化疗敏感性。在本研究中，VP-16诱导的RBL-2H3细胞凋亡伴随着Akt和ERK的激活。 PI3K 抑制剂 LY294002（而非 ERK 抑制剂 PD98059）增强了细胞凋亡。此外，还检测到Cbl-b的下调。 Cbl-b 的过度表达通过抑制 Akt 活性显着增强 VP-16 诱导的细胞凋亡，而显性失活 (DN) RING Finger 结构域突变则完全消除了这种增强作用。另一方面，Cbl-b 增强了 ERK 活性，并且 ERK 抑制剂 PD98059 逆转了 Cbl-b 增强的细胞凋亡。 Ara-c处理过程中也显示出一致的结果。这些观察结果表明，Cbl-b 可能通过抑制 Akt 和激活 ERK 促进 VP-16 或 Ara-c 诱导的 RBL-2H3 凋亡。
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.