Cellular senescence and protein degradation Breaking down cancer
Cellular senescence and protein degradation Breaking down cancer
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DOI：
10.4161/cc.29335
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发表时间：
2014-06-15
期刊：
影响因子：
4.3
通讯作者：
Ferbeyre, Gerardo
中科院分区：
文献类型：
--
作者：
Deschenes-Simard, Xavier;Lessard, Frederic;Ferbeyre, Gerardo
自噬和泛素-蛋白酶体途径（UPP）是真核细胞中主要的蛋白质降解系统。前者介导大量非特异性降解，而UPP允许特异性蛋白质的快速降解。这两个系统已被证明在肿瘤发生中发挥作用，并且对开发抑制蛋白质降解的治疗剂的兴趣正在稳步增长。然而，新出现的数据指出自噬在细胞衰老中起关键作用，这是一种已建立的肿瘤抑制机制。最近，由UPP介导的选择性蛋白质降解过程也被证明有助于衰老表型。这一过程受到E3泛素连接酶、去泛素酶和靶蛋白翻译后修饰的严格调控。说明UPP的复杂性，超过600个人类基因已被证明编码E3泛素连接酶，超过蛋白激酶的数量。然而，我们对蛋白酶体依赖的蛋白质降解作为细胞背景下的调节过程，如癌症和衰老的认识仍然非常有限。在这里，我们讨论了蛋白质降解在衰老中的意义，并试图将这种功能与在癌细胞中观察到的蛋白质降解模式联系起来。
Autophagy and the ubiquitin-proteasome pathway (UPP) are the major protein degradation systems in eukaryotic cells. Whereas the former mediate a bulk nonspecific degradation, the UPP allows a rapid degradation of specific proteins. Both systems have been shown to play a role in tumorigenesis, and the interest in developing therapeutic agents inhibiting protein degradation is steadily growing. However, emerging data point to a critical role for autophagy in cellular senescence, an established tumor suppressor mechanism. Recently, a selective protein degradation process mediated by the UPP was also shown to contribute to the senescence phenotype. This process is tightly regulated by E3 ubiquitin ligases, deubiquitinases, and several post-translational modifications of target proteins. Illustrating the complexity of UPP, more than 600 human genes have been shown to encode E3 ubiquitin ligases, a number which exceeds that of the protein kinases. Nevertheless, our knowledge of proteasome-dependent protein degradation as a regulated process in cellular contexts such as cancer and senescence remains very limited. Here we discuss the implications of protein degradation in senescence and attempt to relate this function to the protein degradation pattern observed in cancer cells.