Aurora B激酶直接磷酸化并稳定MYC来促进T细胞白血病的发生
2020-02-14   阅读:439   来源:细胞

近日,武汉大学中南医院刘胡丹研究小组发现,Aurora B激酶直接磷酸化并稳定MYC来促进T细胞白血病的发生。相关论文2020年2月10日发表于国际学术期刊《癌细胞》。

研究人员发现了Aurora B激酶(AURKB)和MYC之间相互激活的分子机制。AURKB在丝氨酸67处直接磷酸化MYC,抵消了GSK3β介导的第58位苏氨酸磷酸化和随后FBXW7介导的蛋白酶体降解。稳定的MYC与T细胞急性淋巴细胞白血病1(TAL1)蛋白协同作用,直接激活AURKB转录,构成一个正向反馈环路,增强了MYC调控的致癌程序。因此,AURKB抑制剂诱导明显的MYC降解,并随强烈的白血病细胞死亡。这些发现揭示了作为T细胞白血病发生的AURKB-MYC调节回路,并为通过AURKB抑制致癌性MYC的治疗靶向提供了依据。
 
据了解,MYC的失调在T细胞急性淋巴细胞白血病(T-ALL)中起着至关重要的作用,但其失调的机制仍然难以捉摸。
 
附:英文原文
 
Title: Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis

Author: Jue Jiang, Jingchao Wang, Ming Yue, Xiaolian Cai, Tianci Wang, Chao Wu, Hexiu Su, Yanwu Wang, Meng Han, Yingchi Zhang, Xiaofan Zhu, Peng Jiang, Peng Li, Yonghua Sun, Wuhan Xiao, Hui Feng, Guoliang Qing, Hudan Liu

Issue&Volume: 2020/02/10

Abstract: Deregulation of MYC plays an essential role in T cell acute lymphoblastic leukemia(T-ALL), yet the mechanisms underlying its deregulation remain elusive. Herein, weidentify a molecular mechanism responsible for reciprocal activation between AuroraB kinase (AURKB) and MYC. AURKB directly phosphorylates MYC at serine 67, counteractingGSK3β-directed threonine 58 phosphorylation and subsequent FBXW7-mediated proteasomaldegradation. Stabilized MYC, in concert with T cell acute lymphoblastic leukemia 1(TAL1), directly activates AURKB transcription, constituting a positive feedforward loop that reinforces MYC-regulatedoncogenic programs. Therefore, inhibitors of AURKB induce prominent MYC degradationconcomitant with robust leukemia cell death. These findings reveal an AURKB-MYC regulatorycircuit that underlies T cell leukemogenesis, and provide a rationale for therapeutictargeting of oncogenic MYC via AURKB inhibition.

DOI: 10.1016/j.ccell.2020.01.001

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