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

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

  • Nat Cell Biol. 2017 Oct;19(10):1226-1236. doi: 10.1038/ncb3616.
Xiaofeng Wu 1,  Li-Shu Zhang 1,  Jason Toombs 2 3,  Yi-Chun Kuo 3 4,  John Tyler Piazza 1,  Rubina Tuladhar 1,  Quinn Barrett 1,  Chih-Wei Fan 1,  Xuewu Zhang 3 4,  Loren D Walensky 5 6,  Marcel Kool 7 8,  Steven Y Cheng 9 10,  Rolf Brekken 2 3,  Joseph T Opferman 11,  Douglas R Green 12,  Tudor Moldoveanu 13 14,  Lawrence Lum 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 2 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 3 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
  • 5 Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 6 Department of Pediatrics, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
  • 7 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
  • 8 German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
  • 9 Department of Developmental Genetics, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
  • 10 Center for Regenerative Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
  • 11 Cell &Molecular Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
  • 12 Immunology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
  • 13 Structural Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
  • 14 Chemical Biology and Therapeutics Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.
PMID: 28945232 DOI: 10.1038/ncb3616
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.

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