Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
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DOI：
10.1182/blood-2009-11-251074
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发表时间：
2010-09-02
期刊：
影响因子：
20.3
通讯作者：
Keller, Ulrich
中科院分区：
文献类型：
--
作者：
den Hollander, Juergen;Rimpi, Sara;Keller, Ulrich
Myc癌蛋白部分通过控制关键细胞周期调节因子的转录来促进细胞的持续生长。在这里，我们报告说，c-Myc调节极光A和B激酶（Aurka和Aurkb）的表达，Aurka和Aurkb的转录和蛋白质水平在Myc驱动的B细胞淋巴瘤在小鼠和人类都高度升高。Myc对Aurka的诱导是转录的，并通过E-box直接介导，而Aurkb是间接调节的。用选择性Aurora激酶抑制剂阻断Aurka/B激酶活性可触发Myc诱导的淋巴瘤的短暂有丝分裂停滞、多倍化和凋亡。这些表型选择性地绕过激酶抑制剂抗性Aurkb突变体，表明Aurkb是Myc背景下的主要治疗靶点。重要的是，由Aurk抑制引起的细胞凋亡是p53独立的，这表明Aurka/Aurkb抑制剂将在治疗具有Myc参与和/或p53功能丧失的原发性或复发性恶性肿瘤中显示出功效。（血。2010;116（9）：1498-1505）
Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant-Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function. (Blood. 2010;116(9):1498-1505)