De-ubiquitination of ELK-1 by USP17 potentiates mitogenic gene expression and cell proliferation

Ducker, Charles; Chow, Leo Kam Yuen; Saxton, Janice; Handwerger, Jürgen; McGregor, Alexander; Strahl, Thomas; Layfield, Robert; Shaw, Peter E.

Abstract

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.

Citation

Ducker, C., Chow, L., Saxton, J., Handwerger, J., McGregor, A., Strahl, T., …Shaw, P. E. (2019). De-ubiquitination of ELK-1 by USP17 potentiates mitogenic gene expression and cell proliferation. Nucleic Acids Research, 47(9), 4495-4508. https://doi.org/10.1093/nar/gkz166

• Journal Article Type: Article
• Acceptance Date: Mar 1, 2019
• Online Publication Date: Mar 11, 2019
• Publication Date: Mar 11, 2019
• Deposit Date: Mar 18, 2019
• Publicly Available Date: Mar 18, 2019
• Journal: Nucleic Acids Research
• Print ISSN: 0305-1048
• Electronic ISSN: 1362-4962
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 47
• Issue: 9
• Pages: 4495-4508
• DOI: https://doi.org/10.1093/nar/gkz166
• Keywords: Biochemistry
• Public URL: https://nottingham-repository.worktribe.com/output/1660895
• Publisher URL: https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkz166/5373032
• Contract Date: Mar 18, 2019