Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation.
Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation.
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三氧化二砷和血管紧张素 II 对 HERG 蛋白表达有抑制作用：PML SUMOylation 作用的证据。
DOI：
10.18632/oncotarget.17563
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发表时间：
2017-07-11
期刊：
影响因子：
--
通讯作者：
Yang BF
中科院分区：
文献类型：
--
作者：
Liu Y;Li D;Nie D;Liu SK;Qiu F;Liu MT;Li YY;Wang JX;Liu YX;Dong CJ;Wu D;Tian W;Yang J;Mu W;Li JT;Zhao D;Wang XF;Chu WF;Yang BF
人类ether-a-go-go-related gene（HERG）通道是治疗药物诱导的长QT综合征的新靶点，该综合征可导致致命的心脏毒性。本研究旨在探讨PML SUMO化及其相关核体（NB）在HERG蛋白表达调控中的可能作用。三氧化二砷（ATO）和血管紧张素II（Ang II）都能够显著降低HERG蛋白表达，同时也增加PML SUMO化并加速PML-NB的形成。将心肌细胞预先暴露于SUMO化化学抑制剂银杏酸或沉默UBC 9抑制PML SUMO化，随后阻止ATO或Ang II诱导的HERG下调。相反，RNF 4的敲低导致PML SUMO化和PML-NB功能的显著增加，进一步促进ATO或Ang II诱导的HERG蛋白下调。从机制上讲，ATO或Ang II引起的PML SUMO化增加显著增强PML-NB中PML和Pin 1复合物的形成，导致TGF-β1蛋白上调，最终通过激活蛋白激酶A抑制HERG表达。目前的工作揭示了HERG蛋白表达的一种新的分子机制，并表明PML SUMO化是药物获得性心律失常发生的关键步骤。
The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II. Conversely, knockdown of RNF4 led to a remarkable increase in PML SUMOylation and the function of PML-NBs, further promoting ATO- or Ang II-induced HERG protein downregulation. Mechanistically, an increase in PML SUMOylation by ATO or Ang II dramatically enhanced the formation of PML and Pin1 complexes in PML-NBs, leading to the upregulation of TGF-β1 protein, eventually inhibiting HERG expression through activation of protein kinase A. The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.
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DOI：
10.1152/ajpheart.01252.2008
发表时间：
2009-05-01
影响因子：
4.8
作者：
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通讯作者：
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