A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome
A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome
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DOI：
10.1152/ajpheart.01052.2008
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发表时间：
2008-12-01
影响因子：
4.8
通讯作者：
Wang, Xuejun
中科院分区：
文献类型：
--
作者：
Liu, Jinbao;Zheng, Hanqiao;Wang, Xuejun
治疗剂量的阿霉素通过作用于泛素化装置和蛋白酶体来激活泛素-蛋白酶体系统介导的蛋白水解。Am J Physiol Heart Circ Physiol 295：H2541-H2550，2008; doi：10.1152/ajpheart.01052.2008.-泛素蛋白酶体系统（UPS）降解异常蛋白质和大多数不需要的正常蛋白质，从而在细胞内蛋白质稳态中发挥关键作用。蛋白酶体抑制在治疗某些形式的癌症中是有效的，而UPS功能障碍越来越多地涉及许多严重但常见的疾病的发病机制。先前已经显示，阿霉素（Dox）增强UPS替代底物在小鼠心脏中的降解。为了解决潜在的机制，在本研究中，我们报告了1）Dox不仅增强了外源性UPS报告基因（GFPu）的降解，而且还拮抗了蛋白酶体介导的内源性底物（例如，例如，在一个实施例中，β-连环蛋白和c-Jun）; 2）Dox通过增强蛋白酶体功能促进重组UPS体外降解GFPu和c-Jun; 3）治疗相关剂量的Dox直接刺激纯化的20 S蛋白酶体的肽酶活性; Dox通过转录后机制增加3 T3细胞中热休克蛋白同源物70的E3连接酶COOH末端，而蛋白酶体抑制减少。这些新发现表明，Dox通过直接作用于泛素化装置和蛋白酶体来激活UPS。
A therapeutic dose of doxorubicin activates ubiquitin-proteasome system-mediated proteolysis by acting on both the ubiquitination apparatus and proteasome. Am J Physiol Heart Circ Physiol 295: H2541-H2550, 2008; doi:10.1152/ajpheart.01052.2008.-The ubiquitin proteasome system (UPS) degrades abnormal proteins and most unneeded normal proteins, thereby playing a critical role in protein homeostasis in the cell. Proteasome inhibition is effective in treating certain forms of cancer, while UPS dysfunction is increasingly implicated in the pathogenesis of many severe and yet common diseases. It has been previously shown that doxorubicin (Dox) enhances the degradation of a UPS surrogate substrate in mouse hearts. To address the underlying mechanism, in the present study, we report that 1) Dox not only enhances the degradation of an exogenous UPS reporter (GFPu) but also antagonizes the proteasome inhibitor-induced accumulation of endogenous substrates (e. g., beta-catenin and c-Jun) of the UPS in cultured NIH 3T3 cells and cardiomyocytes; 2) Dox facilitates the in vitro degradation of GFPu and c-Jun by the reconstituted UPS via the enhancement of proteasomal function; 3) Dox at a therapeutically relevant dose directly stimulates the peptidase activities of purified 20S proteasomes; and 4) Dox increases, whereas proteasome inhibition decreases, E3 ligase COOH-terminus of heat shock protein cognate 70 in 3T3 cells via a posttranscriptional mechanism. These new findings suggest that Dox activates the UPS by acting directly on both the ubiquitination apparatus and proteasome.