SPOP in Cancer: Phenomena, Mechanisms and Its Role in Therapeutic Implications.
SPOP in Cancer: Phenomena, Mechanisms and Its Role in Therapeutic Implications.
复制标题
癌症中的 SPOP：现象、机制及其在治疗意义中的作用
作者：
斑点型POZ蛋白（Speckle-type POZ protein，SPOP）是一种以Cullin 3为底物的E3泛素连接酶接头蛋白，在泛素介导的蛋白质降解中起重要作用。最近，SPOP引起了主要的研究关注，因为它在一系列癌症中经常发生突变，突出了多效性致瘤效应和与治疗耐药性的关联。在结构上，SPOP包含许多SPOP底物的功能关键的N-末端meprin和TRAF同源（MATH）结构域。SPOP具有两个其他结构域，包括内部Bric-a-brac-Tramtrack/Broad（BTB）结构域，其与SPOP二聚化和cullin 3结合，以及C-末端核定位序列（NLS）。SPOP介导的蛋白水解的失调与不同癌症的发展和进展相关，因为SPOP功能的异常通过以肿瘤特异性方式靶向癌蛋白或肿瘤抑制因子来失调细胞信号传导途径。SPOP还通过其在DNA损伤反应和DNA复制中的作用参与基因组稳定性。最近的研究表明，SPOP的表达可以通过多种方式进行调节。本文就SPOP在肿瘤中的作用及如何设计合理的治疗靶点作一综述。
Speckle-type POZ (pox virus and zinc finger protein) protein (SPOP) is a cullin 3-based E3 ubiquitin ligase adaptor protein that plays a crucial role in ubiquitin-mediated protein degradation. Recently, SPOP has attracted major research attention as it is frequently mutated in a range of cancers, highlighting pleiotropic tumorigenic effects and associations with treatment resistance. Structurally, SPOP contains a functionally critical N-terminal meprin and TRAF homology (MATH) domain for many SPOP substrates. SPOP has two other domains, including the internal Bric-a-brac-Tramtrack/Broad (BTB) domain, which is linked with SPOP dimerization and binding to cullin3, and a C-terminal nuclear localization sequence (NLS). The dysregulation of SPOP-mediated proteolysis is associated with the development and progression of different cancers since abnormalities in SPOP function dysregulate cellular signaling pathways by targeting oncoproteins or tumor suppressors in a tumor-specific manner. SPOP is also involved in genome stability through its role in the DNA damage response and DNA replication. More recently, studies have shown that the expression of SPOP can be modulated in various ways. In this review, we summarize the current understanding of SPOP’s functions in cancer and discuss how to design a rational therapeutic target.