Transcription and Molecular Signalling Laboratory, School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Nucleic Acids Res. 2019 May 21;47(9):4495-4508. doi: 10.1093/nar/gkz166.
ELK-1 is a transcription factor involved in ERK-induced cellular proliferation. Here, we show that its transcriptional activity is modulated by ubiquitination at lysine 35 (K35). The level of ubiquitinated ELK-1 rises in mitogen-deprived cells and falls upon mitogen stimulation or oncogene expression. Ectopic expression of USP17, a cell cycle-dependent deubiquitinase, decreases ELK-1 ubiquitination and up-regulates ELK-1 target-genes with a concomitant increase in cyclin D1 expression. In contrast, USP17 depletion attenuates ELK-1-dependent gene expression and slows cell proliferation. The reduced rate of proliferation upon USP17 depletion appears to be a direct effect of ELK-1 ubiquitination because it is rescued by an ELK-1(K35R) mutant refractory to ubiquitination. Overall, our results show that ubiquitination of ELK-1 at K35, and its reversal by USP17, are important mechanisms in the regulation of nuclear ERK signalling and cellular proliferation. Our findings will be relevant for tumours that exhibit elevated USP17 expression and suggest a new target for intervention.
ELK-1 是一种转录因子，参与 ERK 诱导的细胞增殖。在这里，我们表明其转录活性受到赖氨酸 35（K35）泛素化的调节。在有丝分裂剥夺的细胞中，泛素化的 ELK-1 水平升高，而在有丝分裂刺激或致癌基因表达时则降低。细胞周期依赖性去泛素化酶 USP17 的异位表达降低了 ELK-1 的泛素化，并上调了 ELK-1 靶基因，同时 cyclin D1 的表达增加。相比之下，USP17 的耗竭会减弱 ELK-1 依赖的基因表达并减缓细胞增殖。USP17 耗竭后增殖率降低似乎是 ELK-1 泛素化的直接影响，因为它可以通过对泛素化无反应的 ELK-1（K35R）突变体得到挽救。总的来说，我们的研究结果表明，ELK-1 在 K35 的泛素化及其由 USP17 逆转，是核 ERK 信号和细胞增殖调节的重要机制。我们的发现将与那些表现出 USP17 表达升高的肿瘤有关，并为干预提供了一个新的靶点。
