Increased BIK expression following ERK1/2 pathway inhibition is a consequence of G1 cell cycle arrest and not a direct effect on BIK protein stability

BIK is a pro-apoptotic BH3-only protein and a member of the BCL2 protein family. It has recently been proposed that BIK abundance is controlled by ERK1/2-catalysed phosphorylation, which targets the protein for proteasome-dependent destruction. Here we have examined ERK1/2-dependent regulation of BIK drawing comparisons with BIMEL, a well-known target of ERK1/2. In many ERK1/2-dependent tumour cell lines inhibition of BRAFV600E or MEK1/2 had very little effect on BIK expression, whereas BIMEL was strongly up-regulated. In some cell lines we did observe a modest increase in BIK expression; however, this was not apparent until ~16 hours or later, whereas BIMEL expression increased rapidly within a few hours. Whilst 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 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 that results from inhibition of ...

Source: BJ Cell - February 17, 2014 Category: Biochemistry Authors: M J. Sale, S J. Cook Tags: BJ Signal Source Type: research