Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation
Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation
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DOI：
10.1038/leu.2010.114
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发表时间：
2010-08-01
期刊：
影响因子：
11.4
通讯作者：
Kraemer, O. H.
中科院分区：
文献类型：
--
作者：
Buchwald, M.;Pietschmann, K.;Kraemer, O. H.
III 类受体酪氨酸激酶 FMS 样酪氨酸激酶 3 (FLT3) 调节正常造血和免疫功能。尽管如此，组成型活性突变体 FLT3 (FLT3-ITD) 会导致转化，并与急性髓系白血病 (AML) 患者的不良预后相关。组蛋白脱乙酰酶抑制剂 (HDACi) 可以抵消失调的基因表达谱并降低癌蛋白的稳定性，这使它们成为 AML 治疗的候选药物。然而，这些药物具有多效性，并且通常不清楚它们如何纠正致癌转录组和蛋白质组。我们在此报告，用 HDACi LBH589 处理 AML 细胞会诱导泛素结合酶 UBCH8 和 FLT3-ITD 降解。功能获得和丧失的方法表明，UBCH8 和泛素连接酶 SIAH1 与 FLT3-ITD 发生物理相互作用，并以 FLT3-ITD 为目标进行蛋白酶体降解。但这些泛素化酶对野生型 FLT3 的影响明显较小。此外，FLT3磷酸化的生理学和药理学刺激、FLT3-ITD自身磷酸化的抑制以及激酶失活的FLT3-ITD的分析表明，酪氨酸磷酸化决定了蛋白酶体对FLT3和FLT3-ITD的降解。这些结果为 HDACi 的抗白血病活性和定位 UBCH8 提供了新的见解，UBCH8 主要参与细胞核内的过程，作为 FLT3-ITD 稳定性和白血病细胞存活的先前未被认识的重要调节剂。白血病 (2010) 24, 1412-1421; doi：10.1038/leu.2010.114； 2010 年 5 月 27 日在线发布
The class III receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) regulates normal hematopoiesis and immunological functions. Nonetheless, constitutively active mutant FLT3 (FLT3-ITD) causally contributes to transformation and is associated with poor prognosis of acute myeloid leukemia (AML) patients. Histone deacetylase inhibitors (HDACi) can counteract deregulated gene expression profiles and decrease oncoprotein stability, which renders them candidate drugs for AML treatment. However, these drugs have pleiotropic effects and it is often unclear how they correct oncogenic transcriptomes and proteomes. We report here that treatment of AML cells with the HDACi LBH589 induces the ubiquitin-conjugating enzyme UBCH8 and degradation of FLT3-ITD. Gain-and loss-of-function approaches show that UBCH8 and the ubiquitin-ligase SIAH1 physically interact with and target FLT3-ITD for proteasomal degradation. These ubiquitinylating enzymes though have a significantly lesser effect on wild-type FLT3. Furthermore, physiological and pharmacological stimulation of FLT3 phosphorylation, inhibition of FLT3-ITD autophosphorylation and analysis of kinase-inactive FLT3-ITD revealed that tyrosine phosphorylation determines degradation of FLT3 and FLT3-ITD by the proteasome. These results provide novel insights into antileukemic activities of HDACi and position UBCH8, which have been implicated primarily in processes in the nucleus, as a previously unrecognized important modulator of FLT3-ITD stability and leukemic cell survival. Leukemia (2010) 24, 1412-1421; doi:10.1038/leu.2010.114; published online 27 May 2010