A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin
A novel transgenic mouse model reveals deregulation of the ubiquitin-proteasome system in the heart by doxorubicin
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DOI：
10.1096/fj.05-3973fje
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发表时间：
2005-09-01
期刊：
影响因子：
4.8
通讯作者：
Wang, XJ
中科院分区：
文献类型：
--
作者：
Kumarapeli, ARK;Horak, KM;Wang, XJ
泛素-蛋白酶体系统（UPS）介导的蛋白质降解是细胞内大部分蛋白质降解的主要途径，在维持细胞内环境稳定和调节细胞功能方面发挥着重要作用。UPS功能障碍与许多疾病的发病机制有关，包括神经退行性疾病、肌营养不良和心肌病的子集。然而，在体内监测UPS的功能变化仍然是一个挑战，这阻碍了UPS的病理生理学的阐明。我们最近建立了一种新的转基因小鼠模型，它普遍表达UPS的替代蛋白底物。本研究验证了其适用于监测几乎所有主要器官中UPS蛋白水解功能的体内变化。还开发了来自成年转基因小鼠的细胞的原代培养物，并测试了它们在探测UPS参与发病机制中的应用。应用这些新建立的体内和体外方法，我们已经证明在本研究中，阿霉素增强UPS在心脏和培养的心肌细胞中的功能，这表明UPS功能亢进可能在阿霉素治疗的急性心脏毒性中发挥重要作用。
Ubiquitin-proteasome system ( UPS) mediated proteolysis is responsible for the degradation of majority of cellular proteins, thereby playing essential roles in maintaining cellular homeostasis and regulating a number of cellular functions. UPS dysfunction was implicated in the pathogenesis of numerous disorders, including neurodegenerative disease, muscular dystrophy, and a subset of cardiomyopathies. However, monitoring in vivo functional changes of the UPS remains a challenge, which hinders the elucidation of UPS pathophysiology. We have recently created a novel transgenic mouse model that ubiquitously expresses a surrogate protein substrate for the UPS. The present study validates its suitability to monitor in vivo changes of UPS proteolytic function in virtually all major organs. Primary culture of cells derived from the adult transgenic mice was also developed and tested for their applications in probing UPS involvement in pathogenesis. Applying these newly established in vivo and in vitro approaches, we have proven in the present study that doxorubicin enhances UPS function in the heart and in cultured cardiomyocytes, suggesting that UPS hyper-function may play an important role in the acute cardiotoxicity of doxorubicin therapy.