Journal
NATURE CELL BIOLOGY
Volume 19, Issue 10, Pages 1226-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3616
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Funding
- Welch Foundation [I-1665]
- CPRIT [RP130212]
- National Cancer Institute of the National Institutes of Health [R01CA168761, R01CA196851, P50-CA70907]
- T32 training grant [5T32CA124334]
- National Basic Research Program of China [2012CB945003]
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Direct interactions between pro-and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1 and BCL-XL. Anti-apoptotic BCL-2 protein/SUFU feedforward signalling promotes cancer cell survival and growth, and can be disabled with BH3 mimetics-small molecules that target anti-apoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators.
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