Chen Hsin-Yi, Chen Ruey-Hwa
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University , Taipei , Taiwan.
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
Front Oncol. 2016 May 2;6:113. doi: 10.3389/fonc.2016.00113. eCollection 2016.
Cullin-RING ubiquitin ligases are the largest E3 ligase family in eukaryotes and are multiprotein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. To date, eight members of the Cullin family proteins have been identified. In the Cul3 ubiquitin ligases, Bric-a-brac/Tramtrack/Broad complex (BTB) domain-containing proteins function as a bridge to connect Cul3 and substrates. While the BTB domain is responsible for Cul3 binding, these proteins usually contain an additional domain for substrate interaction, such as MATH, kelch, Zn finger, and PAM, Highwire, and RPM-1 (PHR domain). With the existence of a large number of BTB proteins in human, the Cul3 ubiquitin ligases ubiquitinate a wide range of substrates involving in diverse cellular functions. In this review, we will discuss recent advances on the functions of Cul3 ubiquitin ligases in cancer development, progression, and therapeutic response and the dysregulation of Cul3-mediated ubiquitination events in human malignancies. In particular, we will focus on three Cul3 substrate adaptors, kelch-like ECH-associated protein (Keap1), kelch-like family member 20 (KLHL20), and speckle type BTB/POZ protein (SPOP), with the intent to highlight novel targets in cancer therapy.
Cullin-RING泛素连接酶是真核生物中最大的E3连接酶家族，是多蛋白复合物。在这些复合物中，Cullin蛋白作为支架连接连接酶的两个功能模块，即催化亚基和底物结合亚基。迄今为止，已鉴定出Cullin家族蛋白的八个成员。在Cul3泛素连接酶中，含Bric-a-brac/Tramtrack/Broad复合物（BTB）结构域的蛋白作为连接Cul3和底物的桥梁。虽然BTB结构域负责与Cul3结合，但这些蛋白通常还含有一个用于与底物相互作用的额外结构域，如MATH、kelch、锌指以及PAM、Highwire和RPM-1（PHR结构域）。由于人类中存在大量BTB蛋白，Cul3泛素连接酶可泛素化涉及多种细胞功能的广泛底物。在本综述中，我们将讨论Cul3泛素连接酶在癌症发生、发展和治疗反应中的功能以及人类恶性肿瘤中Cul3介导的泛素化事件失调的最新进展。特别是，我们将重点关注三种Cul3底物衔接蛋白，即kelch样ECH相关蛋白（Keap1）、kelch样家族成员20（KLHL20）和斑点型BTB/POZ蛋白（SPOP），旨在突出癌症治疗中的新靶点。
