De-ubiquitination of ELK-1 by USP17 potentiates mitogenic gene expression and cell proliferation.
Cell Cycle
/ genetics
Cell Nucleus
/ genetics
Cell Proliferation
/ genetics
Endopeptidases
/ genetics
Gene Expression Regulation
/ genetics
HEK293 Cells
HeLa Cells
Humans
Mitosis
/ genetics
Phosphorylation
Signal Transduction
/ genetics
Transcription Factors
/ genetics
Ubiquitination
/ genetics
ets-Domain Protein Elk-1
/ genetics
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 05 2019
21 05 2019
Historique:
accepted:
01
03
2019
revised:
26
02
2019
received:
21
08
2018
pubmed:
12
3
2019
medline:
22
11
2019
entrez:
12
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30854565
pii: 5373032
doi: 10.1093/nar/gkz166
pmc: PMC6511843
doi:
Substances chimiques
ELK1 protein, human
0
Transcription Factors
0
ets-Domain Protein Elk-1
0
Endopeptidases
EC 3.4.-
USP17L2 protein, human
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4495-4508Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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