Journal Article

DKFZ-2017-06261

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor.

Wu, X. ; Zhang, L.-S. ; Toombs, J. ; Kuo, Y.-C. ; Piazza, J. T. ; Tuladhar, R. ; Barrett, Q. ; Fan, C.-W. ; Zhang, X. ; Walensky, L. D. ; Kool, M.DKFZ* ; Cheng, S. Y. ; Brekken, R. ; Opferman, J. T. ; Green, D. R. ; Moldoveanu, T. ; Lum, L.

2017
Nature America New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): Antineoplastic Agents ; BCL2 protein, human ; BCL2L1 protein, human ; Bax protein (53-86) ; Bcl2l1 protein, mouse ; GLI1 protein, human ; Gli protein, mouse ; MCL1 protein, human ; Mcl1 protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; Peptide Fragments ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Repressor Proteins ; SUFU protein, human ; Sufu protein, mouse ; Tumor Suppressor Proteins ; Zinc Finger Protein GLI1 ; bcl-X Protein ; Bcl2 protein, mouse

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 15 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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