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
AffiliationsContributionsCorresponding author Nature Cell Biology 19, 1226–1236 (2017) doi:10.1038/ncb3616 Received 10 April 2016 Accepted 17 August 2017
Published online 25 September 2017
Abstract Abstract• References• Author information• Supplementary information 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.
Affiliations Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Xiaofeng Wu, Li-shu Zhang, John Tyler Piazza, Rubina Tuladhar, Quinn Barrett, Chih-wei Fan & Lawrence Lum
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Jason Toombs & Rolf Brekken
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Jason Toombs, Yi-Chun Kuo, Xuewu Zhang & Rolf Brekken
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA Yi-Chun Kuo & Xuewu Zhang
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA Loren D. Walensky
Department of Pediatrics, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA Loren D. Walensky
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany Marcel Kool
German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany Marcel Kool
Department of Developmental Genetics, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China Steven Y. Cheng
Center for Regenerative Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China Steven Y. Cheng
Cell & Molecular Biology Department, St Jude Children’s Hospital, Memphis, Tennessee 38105, USA Joseph T. Opferman
Immunology Department, St Jude Children’s Hospital, Memphis, Tennessee 38105, USA Douglas R. Green
Structural Biology Department, St Jude Children’s Hospital, Memphis, Tennessee 38105, USA Tudor Moldoveanu
Chemical Biology and Therapeutics Department, St Jude Children’s Hospital, Memphis, Tennessee 38105, USA Tudor Moldoveanu
Ask yourself why so many are trying to stop and delay PS Targeting?
Also ask.. Lots of important names above ...and what brought Dr Loren D. Lorensky over to the collaborations with Dr Rolf Brekken and you will have a very good idea after this video which is quite inspiring when you hear it and yes, Dr Jay Bradner and Dr Nathanael Gray is mentioned and remember:
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