%0 Journal Article
%A Wu, Xiaofeng
%A Zhang, Li-Shu
%A Toombs, Jason
%A Kuo, Yi-Chun
%A Piazza, John Tyler
%A Tuladhar, Rubina
%A Barrett, Quinn
%A Fan, Chih-Wei
%A Zhang, Xuewu
%A Walensky, Loren D
%A Kool, Marcel
%A Cheng, Steven Y
%A Brekken, Rolf
%A Opferman, Joseph T
%A Green, Douglas R
%A Moldoveanu, Tudor
%A Lum, Lawrence
%T Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor.
%J Nature cell biology
%V 19
%N 10
%@ 1476-4679
%C New York, NY
%I Nature America
%M DKFZ-2017-06261
%P 1226 - 1236
%D 2017
%X 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.
%K Antineoplastic Agents (NLM Chemicals)
%K BCL2 protein, human (NLM Chemicals)
%K BCL2L1 protein, human (NLM Chemicals)
%K Bax protein (53-86) (NLM Chemicals)
%K Bcl2l1 protein, mouse (NLM Chemicals)
%K GLI1 protein, human (NLM Chemicals)
%K Gli protein, mouse (NLM Chemicals)
%K MCL1 protein, human (NLM Chemicals)
%K Mcl1 protein, mouse (NLM Chemicals)
%K Myeloid Cell Leukemia Sequence 1 Protein (NLM Chemicals)
%K Peptide Fragments (NLM Chemicals)
%K Proto-Oncogene Proteins (NLM Chemicals)
%K Proto-Oncogene Proteins c-bcl-2 (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%K SUFU protein, human (NLM Chemicals)
%K Sufu protein, mouse (NLM Chemicals)
%K Tumor Suppressor Proteins (NLM Chemicals)
%K Zinc Finger Protein GLI1 (NLM Chemicals)
%K bcl-X Protein (NLM Chemicals)
%K Bcl2 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:28945232
%2 pmc:PMC5657599
%R 10.1038/ncb3616
%U https://inrepo02.dkfz.de/record/131629