Chen Yu, Zhou Chi, Ji Wei, Mei Zhichao, Hu Bo, Zhang Wei, Zhang Dawei, Wang Jing, Liu Xing, Ouyang Gang, Zhou Jiangang, Xiao Wuhan
The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, 430072 Wuhan, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, 430072 Wuhan, China.
Nat Commun. 2016 Mar 24;7:11057. doi: 10.1038/ncomms11057.
Increasing evidence supports that ELL (eleven-nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor.
越来越多的证据支持ELL（富含11 - 19位赖氨酸的白血病蛋白）是转录延伸的关键调节因子，但ELL在哺乳动物中的生理功能仍不清楚。在这里，我们表明ELL作为一种E3泛素连接酶，靶向c-Myc进行蛋白酶体降解。此外，我们确定UbcH8在该途径中作为泛素结合酶。ELL的半胱氨酸595是该酶的活性位点；将其突变为丙氨酸（C595A）使该蛋白无法促进c-Myc的泛素化和降解。ELL介导的c-Myc降解抑制c-Myc依赖的转录活性和细胞增殖，也抑制c-Myc依赖的异种移植肿瘤生长。相反，ELL（C595A）突变体不仅失去抑制细胞增殖和异种移植肿瘤生长的能力，还促进肿瘤转移。因此，我们的工作揭示了ELL作为c-Myc的E3泛素连接酶和潜在肿瘤抑制因子的先前未被认识的功能。
