Skp2 通路：癌症治疗的关键靶点。
The Skp2 Pathway: A Critical Target for Cancer Therapy.
机构信息
Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA.
National Capital Consortium, Department of Defense, Washington DC, 20307, USA; Institute for Complex Systems, HealthNovations International, Houston, TX, 77089, USA; Center for Cancer Research, National Institutes of Health, Bethesda, MD, 20814, USA; Center on Genomics, Vulnerable Populations, and Health Disparities, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA.
出版信息
Semin Cancer Biol. 2020 Dec;67(Pt 2):16-33. doi: 10.1016/j.semcancer.2020.01.013. Epub 2020 Feb 1.
Strictly regulated protein degradation by ubiquitin-proteasome system (UPS) is essential for various cellular processes whose dysregulation is linked to serious diseases including cancer. Skp2, a well characterized component of Skp2-SCF E3 ligase complex, is able to conjugate both K48-linked ubiquitin chains and K63-linked ubiquitin chains on its diverse substrates, inducing proteasome mediated proteolysis or modulating the function of tagged substrates respectively. Overexpression of Skp2 is observed in various human cancers associated with poor survival and adverse therapeutic outcomes, which in turn suggests that Skp2 engages in tumorigenic activity. To that end, the oncogenic properties of Skp2 are demonstrated by various genetic mouse models, highlighting the potential of Skp2 as a target for tackling cancer. In this article, we will describe the downstream substrates of Skp2 as well as upstream regulators for Skp2-SCF complex activity. We will further summarize the comprehensive oncogenic functions of Skp2 while describing diverse strategies and therapeutic platforms currently available for developing Skp2 inhibitors.
严格调控的蛋白降解通过泛素-蛋白酶体系统 (UPS) 对各种细胞过程至关重要，其失调与包括癌症在内的严重疾病有关。Skp2 是 Skp2-SCF E3 连接酶复合物的一个特征组件，能够在其各种底物上连接 K48 连接的泛素链和 K63 连接的泛素链，分别诱导蛋白酶体介导的蛋白水解或调节标记底物的功能。Skp2 的过表达在与不良预后相关的各种人类癌症中观察到，这反过来表明 Skp2 参与了致癌活性。为此，各种遗传小鼠模型证明了 Skp2 的致癌特性，突出了 Skp2 作为治疗癌症的靶点的潜力。在本文中，我们将描述 Skp2 的下游底物以及 Skp2-SCF 复合物活性的上游调节剂。我们将进一步总结 Skp2 的全面致癌功能，同时描述目前可用于开发 Skp2 抑制剂的各种策略和治疗平台。
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