Thomas Jane J, Abed Mona, Heuberger Julian, Novak Rostislav, Zohar Yaniv, Beltran Lopez Angela P, Trausch-Azar Julie S, Ilagan Ma Xenia G, Benhamou David, Dittmar Gunnar, Kopan Raphael, Birchmeier Walter, Schwartz Alan L, Orian Amir
Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
Cell Rep. 2016 Sep 20;16(12):3388-3400. doi: 10.1016/j.celrep.2016.08.024.
Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate's phosphorylation, rather than SUMOylation, and binding to RNF4's arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.
泛素化调节对癌症发展至关重要的信号通路，并且在许多情况下，将蛋白质作为降解靶点。在此，我们报告RNF4介导的泛素化可稳定原本寿命短暂的致癌转录因子，包括β-连环蛋白、Myc、c-Jun和Notch胞内域（N-ICD）蛋白。RNF4增强这些因子的转录活性以及Wnt和Notch依赖的基因表达。虽然RNF4是一种靶向SUMO的泛素连接酶，但蛋白质稳定化需要底物的磷酸化而非SUMO化，以及与RNF4富含精氨酸的基序结构域结合。稳定化还涉及生成异常的多聚泛素链以及RNF4与染色质的对接。从生物学角度来看，RNF4增强肿瘤表型，对癌细胞存活至关重要。高水平的RNF4 mRNA与一部分乳腺癌患者的不良生存相关，并且在30%的人类结肠腺癌中RNF4蛋白水平升高。因此，RNF4依赖的泛素化将瞬时磷酸化信号转化为长期的蛋白质稳定化，导致癌蛋白激活增强。
