MYC is a major determinant of mitotic cell fate
Topham, C, Tighe, A, Ly, P, Bennett, A, Sloss, O, Nelson, L, Ridgway, RA, Huels, D, Littler, S, Schandl, C, Sun, Y, Bechi, B, Procter, DJ, Sansom, OJ, Cleveland, DW and Taylor, SS 2015, 'MYC is a major determinant of mitotic cell fate' , Cancer Cell, 28 (1) , pp. 129-140.
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Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents.
|Schools:||Schools > School of Environment and Life Sciences > Biomedical Research Centre|
|Journal or Publication Title:||Cancer Cell|
|Funders:||Cancer Research UK, Medical Research Council (MRC), Wellcome Trust|
|Depositing User:||C Topham|
|Date Deposited:||22 Dec 2015 15:19|
|Last Modified:||22 Dec 2015 15:19|
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