Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase
Haploinsufficient tumor suppressor Tip60 negatively regulates oncogenic Aurora B kinase
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DOI：
10.1007/s12038-019-9963-6
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发表时间：
2019-12-01
影响因子：
2.9
通讯作者：
Kundu, Tapas K.
中科院分区：
文献类型：
--
作者：
Bose, Arnab;Sudevan, Surabhi;Kundu, Tapas K.
极光激酶代表一组丝氨酸/苏氨酸激酶，其是有丝分裂的关键调节剂。Aurora激酶B（Aurk B）表达失调，源于基因组扩增、基因转录增加或其变构激活剂的过表达，能够启动和维持恶性表型。虽然AurkB在细胞中的水平是精心策划的，但缺乏与其独立于有丝分裂的稳定性或活性相关的研究。我们报告说，AurkB在体外进行乙酰化的赖氨酸乙酰转移酶（KATs）属于不同的家庭，即p300和Tip 60。单倍不足肿瘤抑制因子Tip 60乙酰化AurkB激酶结构域中两个高度保守的赖氨酸残基，这不仅影响蛋白质的稳定性，而且影响其激酶活性。这些结果表明，如在癌性条件下观察到的，Tip 60下调后AurkB的“总体活性”增加的可能结果。因此，目前的工作揭示了AurkB和Tip 60之间的重要功能相互作用，其脆弱性可能是致癌的初始事件。
The Aurora kinases represent a group of serine/threonine kinases which are crucial regulators of mitosis. Dysregulated Aurora kinase B (AurkB) expression, stemming from genomic amplification, increased gene transcription or overexpression of its allosteric activators, is capable of initiating and sustaining malignant phenotypes. Although AurkB level in cells is well-orchestrated, studies that relate to its stability or activity, independent of mitosis, are lacking. We report that AurkB undergoes acetylation in vitro by lysine acetyltransferases (KATs) belonging to different families, namely by p300 and Tip60. The haploinsufficient tumor suppressor Tip60 acetylates two highly conserved lysine residues within the kinase domain of AurkB which not only impinges the protein stability but also its kinase activity. These results signify a probable outcome on the increase in "overall activity" of AurkB upon Tip60 downregulation, as observed under cancerous conditions. The present work, therefore, uncovers an important functional interplay between AurkB and Tip60, frailty of which may be an initial event in carcinogenesis.