Intracellular protein degradation from a vague idea through the lysosome and the ubiquitin-proteasome system and on to human diseases and drug targeting
Intracellular protein degradation from a vague idea through the lysosome and the ubiquitin-proteasome system and on to human diseases and drug targeting
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DOI：
10.1196/annals.1402.078
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Ciechanover, Aaron
中科院分区：
文献类型：
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作者：
Ciechanover, Aaron
在20世纪50年代至80年代期间，科学家们主要关注遗传密码如何转录为RNA并翻译为蛋白质，但蛋白质如何降解仍然是一个被忽视的研究领域。随着Christian de Duve发现溶酶体，人们认为细胞蛋白质在这个细胞器内降解。然而，一些独立的实验证据强烈表明，细胞内蛋白水解主要是非溶酶体，但涉及的机制仍然不清楚。泛素-蛋白酶体系统的发现解决了这个谜团。我们现在认识到，遍在蛋白和蛋白酶体介导的细胞内蛋白质降解参与多种细胞过程的调节，例如细胞周期和分裂、转录因子的调节以及细胞质量控制的保证。毫不奇怪，系统中的畸变与许多人类疾病、恶性肿瘤和神经退行性疾病的发病机制有关，这导致随后越来越多的努力开发基于机制的药物;其中一种已经在使用中。
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve, it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely nonlysosomal, but the mechanisms involved had remained obscure. The discovery of the ubiquitin-proteasome system resolved this enigma. We now recognize that ubiquitin- and proteasome-mediated degradation of intracellular proteins is involved in the regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many human diseases, malignancies, and neurodegenerative disorders among them, which led subsequently to an increasing effort to develop mechanism-based drugs; one is already in use.