Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor

Xiaofeng Wu, Li Shu Zhang, Jason Toombs, Yi Chun Kuo, John Tyler Piazza, Rubina Tuladhar, Quinn Barrett, Chih Wei Fan, Xuewu Zhang, Loren D. Walensky, Marcel Kool, Steven Y. Cheng, Rolf Brekken, Joseph T. Opferman, Douglas R. Green, Tudor Moldoveanu, Lawrence Lum

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1226-1236
Number of pages11
JournalNature Cell Biology
Volume19
Issue number10
DOIs
StatePublished - Sep 29 2017

ASJC Scopus subject areas

  • Cell Biology

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    Wu, X., Zhang, L. S., Toombs, J., Kuo, Y. C., Piazza, J. T., Tuladhar, R., Barrett, Q., Fan, C. W., Zhang, X., Walensky, L. D., Kool, M., Cheng, S. Y., Brekken, R., Opferman, J. T., Green, D. R., Moldoveanu, T., & Lum, L. (2017). Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor. Nature Cell Biology, 19(10), 1226-1236. https://doi.org/10.1038/ncb3616