BIK (BCL2-interacting killer) is a pro-apoptotic BH3 (BCL2 homology domain 3)-only protein and a member of the BCL2 protein family. It was proposed recently that BIK abundance is controlled by ERK1/2 (extracellular-signal-regulated kinase 1/2)-catalysed phosphorylation, which targets the protein for proteasome-dependent destruction. In the present study, we examined ERK1/2-dependent regulation of BIK, drawing comparisons with BIMEL (BCL2-interacting mediator of cell death; extra long), a well-known target of ERK1/2. In many ERK1/2-dependent tumour cell lines, inhibition of BRAFV600E (v-raf murine sarcoma viral oncogene homologue B1, V600E mutation) or MEK1/2 (mitogen-activated protein kinase/ERK kinase 1/2) had very little effect on BIK expression, whereas BIMEL was strongly up-regulated. In some cell lines we observed a modest increase in BIK expression; however, this was not apparent until ~16 h or later, whereas BIMEL expression increased rapidly within a few hours. Although BIK was degraded by the proteasome, we found no evidence that this was regulated by ERK1/2 signalling. Rather, the delayed increase in BIK expression was prevented by actinomycin D, and was accompanied by increases in BIK mRNA. Finally, the delayed increase in BIK expression following ERK1/2 inhibition was phenocopied by a highly selective CDK4/6 (cyclin-dependent kinases 4 and 6) inhibitor, which caused a strong G1 cell-cycle arrest without inhibiting ERK1/2 signalling. In contrast, BIMEL expression was induced by ERK1/2 inhibition, but not by CDK4/6 inhibition. We conclude that BIK expression is not subject to direct regulation by the ERK1/2 pathway; rather, we propose that BIK expression is cell-cycle-dependent and increases as a consequence of the G1 cell-cycle arrest which results from inhibition of ERK1/2 signalling.
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Research Article|
April 11 2014
The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G1 cell-cycle arrest and not a direct effect on BIK protein stability
Matthew J. Sale;
Matthew J. Sale
1
*Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
1Correspondence may be addressed to either of these authors (email matthew.sale@babraham.ac.uk or simon.cook@babraham.ac.uk).
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Simon J. Cook
Simon J. Cook
1
*Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
1Correspondence may be addressed to either of these authors (email matthew.sale@babraham.ac.uk or simon.cook@babraham.ac.uk).
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Publisher: Portland Press Ltd
Received:
October 10 2013
Revision Received:
January 31 2014
Accepted:
February 17 2014
Accepted Manuscript online:
February 17 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (3): 513–524.
Article history
Received:
October 10 2013
Revision Received:
January 31 2014
Accepted:
February 17 2014
Accepted Manuscript online:
February 17 2014
Citation
Matthew J. Sale, Simon J. Cook; The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G1 cell-cycle arrest and not a direct effect on BIK protein stability. Biochem J 1 May 2014; 459 (3): 513–524. doi: https://doi.org/10.1042/BJ20131346
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