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

Autor: Wu X; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Zhang LS; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Toombs J; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Kuo YC; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Piazza JT; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Tuladhar R; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Barrett Q; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Fan CW; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Zhang X; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Walensky LD; Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.; Department of Pediatrics, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA., Kool M; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany., Cheng SY; Department of Developmental Genetics, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.; Center for Regenerative Medicine, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China., Brekken R; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA., Opferman JT; Cell &Molecular Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA., Green DR; Immunology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA., Moldoveanu T; Structural Biology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA.; Chemical Biology and Therapeutics Department, St Jude Children's Hospital, Memphis, Tennessee 38105, USA., Lum L; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Jazyk: angličtina
Zdroj: Nature cell biology [Nat Cell Biol] 2017 Oct; Vol. 19 (10), pp. 1226-1236. Date of Electronic Publication: 2017 Sep 25.
DOI: 10.1038/ncb3616
Abstrakt: 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.
Databáze: MEDLINE
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