Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Department of Biochemistry and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Cancer Biol Ther. 2022 Dec 31;23(1):348-357. doi: 10.1080/15384047.2022.2061279.
Overexpression of c-myc via increased transcription or decreased protein degradation is common to many cancer etiologies. c-myc protein degradation is mediated by ubiquitin-dependent degradation, and this ubiquitylation is regulated by several E3 ligases. The primary regulator is Fbxw7, which binds to a phospho-degron within c-myc. Here, we identify a new E3 ligase for c-myc, Fbxl8 (F-box and Leucine Rich Repeat Protein 8), as an adaptor component of the SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase complex, for selective c-myc degradation. SCF binds and ubiquitylates c-myc, independent of phosphorylation, revealing that it regulates a pool of c-myc distinct from SCF. Loss of Fbxl8 increases c-myc protein levels, protein stability, and cell division, while overexpression of Fbxl8 reduces c-myc protein levels. Concurrent loss of Fbxl8 and Fbxw7 triggers a robust increase in c-myc protein levels consistent with targeting distinct pools of c-myc. This work highlights new mechanisms regulating c-myc degradation.
c-myc 的过度表达通过转录增加或蛋白质降解减少是许多癌症病因的共同特征。c-myc 蛋白降解是由泛素依赖性降解介导的，这种泛素化受几种 E3 连接酶调节。主要调节剂是 Fbxw7，它与 c-myc 内的磷酸化降解结构域结合。在这里，我们确定了一种新的 c-myc E3 连接酶 Fbxl8（F-box 和亮氨酸丰富重复蛋白 8），作为 SCF（Skp1-Cullin1-F-box 蛋白）泛素连接酶复合物的衔接子组件，用于选择性降解 c-myc。SCF 结合并泛素化 c-myc，与磷酸化无关，表明它调节了与 SCF 不同的 c-myc 池。Fbxl8 的缺失增加了 c-myc 的蛋白水平、蛋白质稳定性和细胞分裂，而过表达 Fbxl8 则降低了 c-myc 的蛋白水平。同时缺失 Fbxl8 和 Fbxw7 会导致 c-myc 蛋白水平显著增加，这与靶向不同的 c-myc 池一致。这项工作强调了调节 c-myc 降解的新机制。
