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.
Highlights
The ETS transcription factor ELK-1 is acutely stimulated by mitogens to establish a gene expression programme commensurate with cell proliferation [1,2,3,4]
The ELK-1-UBQ.K0 conjugate was lost upon mitogen stimulation (Figure 1H, lanes 7–10), suggesting that removal of mono-ubiquitin rather than chain extension and degradation is likely to account for ELK-mUBQ loss
Together these data indicate that ELK-1 can be monoubiquitinated in mitogen-starved cells and that the modification is removed upon ERK signalling and ELK-1 phosphorylation
Summary
The ETS transcription factor ELK-1 is acutely stimulated by mitogens to establish a gene expression programme commensurate with cell proliferation [1,2,3,4]. ELK-1 is one of three ternary complex factors (TCFs) [5,6,7] and binds with serum response factor (SRF) to serum response elements (SREs) in a subset of target gene promoters. Target gene activation by phospho-ELK-1 involves recruitment of active ERK to chromatin [19], phosphorylation of mediator subunits including MED14 [20] and, uniquely for ELK-1 among the TCFs, functional reliance on MED23 [21,22]. In proliferating human ES cells (hESCs), ELK-1 locates to the promoters of differentiation genes independently of ERK and is associated with their repression [2]
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