PMID- 28945232
OWN - NLM
STAT- MEDLINE
DCOM- 20171024
LR  - 20191210
IS  - 1476-4679 (Electronic)
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 19
IP  - 10
DP  - 2017 Oct
TI  - Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by 
      inhibiting the SUFU tumour suppressor.
PG  - 1226-1236
LID - 10.1038/ncb3616 [doi]
AB  - 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.
FAU - Wu, Xiaofeng
AU  - Wu X
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Zhang, Li-Shu
AU  - Zhang LS
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Toombs, Jason
AU  - Toombs J
AD  - Department of Surgery, University of Texas Southwestern Medical Center, Dallas, 
      Texas 75390, USA.
AD  - Department of Pharmacology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Kuo, Yi-Chun
AU  - Kuo YC
AD  - Department of Pharmacology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
AD  - Department of Biochemistry, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Piazza, John Tyler
AU  - Piazza JT
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Tuladhar, Rubina
AU  - Tuladhar R
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Barrett, Quinn
AU  - Barrett Q
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Fan, Chih-Wei
AU  - Fan CW
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Zhang, Xuewu
AU  - Zhang X
AD  - Department of Pharmacology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
AD  - Department of Biochemistry, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Walensky, Loren D
AU  - Walensky LD
AD  - Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Pediatrics, Harvard Medical School, 450 Brookline Avenue, Boston, 
      Massachusetts 02215, USA.
FAU - Kool, Marcel
AU  - Kool M
AD  - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im 
      Neuenheimer Feld 280, Heidelberg 69120, Germany.
AD  - German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, 
      Germany.
FAU - Cheng, Steven Y
AU  - Cheng SY
AD  - Department of Developmental Genetics, Nanjing Medical University, 140 Hanzhong 
      Road, Nanjing, Jiangsu 210029, China.
AD  - Center for Regenerative Medicine, Nanjing Medical University, 140 Hanzhong Road, 
      Nanjing, Jiangsu 210029, China.
FAU - Brekken, Rolf
AU  - Brekken R
AUID- ORCID: 0000-0003-2704-2377
AD  - Department of Surgery, University of Texas Southwestern Medical Center, Dallas, 
      Texas 75390, USA.
AD  - Department of Pharmacology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
FAU - Opferman, Joseph T
AU  - Opferman JT
AD  - Cell &Molecular Biology Department, St Jude Children's Hospital, Memphis, 
      Tennessee 38105, USA.
FAU - Green, Douglas R
AU  - Green DR
AD  - Immunology Department, St Jude Children's Hospital, Memphis, Tennessee 38105, 
      USA.
FAU - Moldoveanu, Tudor
AU  - Moldoveanu T
AD  - Structural Biology Department, St Jude Children's Hospital, Memphis, Tennessee 
      38105, USA.
AD  - Chemical Biology and Therapeutics Department, St Jude Children's Hospital, 
      Memphis, Tennessee 38105, USA.
FAU - Lum, Lawrence
AU  - Lum L
AUID- ORCID: 0000-0002-6119-0253
AD  - Department of Cell Biology, University of Texas Southwestern Medical Center, 
      Dallas, Texas 75390, USA.
LA  - eng
GR  - R01 GM096208/GM/NIGMS NIH HHS/United States
GR  - R01 CA168761/CA/NCI NIH HHS/United States
GR  - R01 CA196851/CA/NCI NIH HHS/United States
GR  - P50 CA070907/CA/NCI NIH HHS/United States
GR  - T32 CA124334/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20170925
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BCL2 protein, human)
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Bax protein (53-86))
RN  - 0 (Bcl2l1 protein, mouse)
RN  - 0 (GLI1 protein, human)
RN  - 0 (Gli1 protein, mouse)
RN  - 0 (MCL1 protein, human)
RN  - 0 (Mcl1 protein, mouse)
RN  - 0 (Myeloid Cell Leukemia Sequence 1 Protein)
RN  - 0 (Peptide Fragments)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Repressor Proteins)
RN  - 0 (SUFU protein, human)
RN  - 0 (Sufu protein, mouse)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 0 (bcl-X Protein)
RN  - 114100-40-2 (Bcl2 protein, mouse)
SB  - IM
CIN - Nat Rev Mol Cell Biol. 2017 Nov;18(11):652-653. PMID: 29018281
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis
MH  - CRISPR-Cas Systems
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Genotype
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Nude
MH  - Molecular Mimicry
MH  - Myeloid Cell Leukemia Sequence 1 Protein/deficiency/genetics/metabolism
MH  - NIH 3T3 Cells
MH  - Neoplasms/drug therapy/genetics/*metabolism/pathology
MH  - Peptide Fragments/metabolism
MH  - Phenotype
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism
MH  - RNA Interference
MH  - Repressor Proteins/genetics/*metabolism
MH  - Signal Transduction
MH  - Time Factors
MH  - *Transcription, Genetic/drug effects
MH  - Transfection
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Zinc Finger Protein GLI1/genetics/metabolism
MH  - bcl-X Protein/genetics/metabolism
PMC - PMC5657599
MID - NIHMS900689
COIS- COMPETING FINANCIAL INTERESTS The authors declare no competing financial 
      interests.
EDAT- 2017/09/26 06:00
MHDA- 2017/10/25 06:00
PMCR- 2018/03/25
CRDT- 2017/09/26 06:00
PHST- 2016/04/10 00:00 [received]
PHST- 2017/08/17 00:00 [accepted]
PHST- 2017/09/26 06:00 [pubmed]
PHST- 2017/10/25 06:00 [medline]
PHST- 2017/09/26 06:00 [entrez]
PHST- 2018/03/25 00:00 [pmc-release]
AID - ncb3616 [pii]
AID - 10.1038/ncb3616 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2017 Oct;19(10):1226-1236. doi: 10.1038/ncb3616. Epub 2017 Sep 25.