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000131629 0247_ $$2ISSN$$a1476-4679
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000131629 037__ $$aDKFZ-2017-06261
000131629 041__ $$aeng
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000131629 1001_ $$aWu, Xiaofeng$$b0
000131629 245__ $$aExtra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor.
000131629 260__ $$aNew York, NY$$bNature America$$c2017
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000131629 520__ $$aDirect interactions between pro- and anti-apoptotic BCL-2 family members form the basis of cell death decision-making at the outer mitochondrial membrane (OMM). Here we report that three anti-apoptotic BCL-2 proteins (MCL-1, BCL-2 and BCL-XL) found untethered from the OMM function as transcriptional regulators of a prosurvival and growth program. Anti-apoptotic BCL-2 proteins engage a BCL-2 homology (BH) domain sequence found in SUFU (suppressor of fused), a tumour suppressor and antagonist of the GLI DNA-binding proteins. BCL-2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL-2, MCL-1 and BCL-XL. Anti-apoptotic BCL-2 protein/SUFU feedforward signalling promotes cancer cell survival and growth, and can be disabled with BH3 mimetics-small molecules that target anti-apoptotic BCL-2 proteins. Our findings delineate a chemical strategy for countering drug resistance in GLI-associated tumours and reveal unanticipated functions for BCL-2 proteins as transcriptional regulators.
000131629 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000131629 650_7 $$2NLM Chemicals$$aAntineoplastic Agents
000131629 650_7 $$2NLM Chemicals$$aBCL2 protein, human
000131629 650_7 $$2NLM Chemicals$$aBCL2L1 protein, human
000131629 650_7 $$2NLM Chemicals$$aBax protein (53-86)
000131629 650_7 $$2NLM Chemicals$$aBcl2l1 protein, mouse
000131629 650_7 $$2NLM Chemicals$$aGLI1 protein, human
000131629 650_7 $$2NLM Chemicals$$aGli protein, mouse
000131629 650_7 $$2NLM Chemicals$$aMCL1 protein, human
000131629 650_7 $$2NLM Chemicals$$aMcl1 protein, mouse
000131629 650_7 $$2NLM Chemicals$$aMyeloid Cell Leukemia Sequence 1 Protein
000131629 650_7 $$2NLM Chemicals$$aPeptide Fragments
000131629 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins
000131629 650_7 $$2NLM Chemicals$$aProto-Oncogene Proteins c-bcl-2
000131629 650_7 $$2NLM Chemicals$$aRepressor Proteins
000131629 650_7 $$2NLM Chemicals$$aSUFU protein, human
000131629 650_7 $$2NLM Chemicals$$aSufu protein, mouse
000131629 650_7 $$2NLM Chemicals$$aTumor Suppressor Proteins
000131629 650_7 $$2NLM Chemicals$$aZinc Finger Protein GLI1
000131629 650_7 $$2NLM Chemicals$$abcl-X Protein
000131629 650_7 $$0114100-40-2$$2NLM Chemicals$$aBcl2 protein, mouse
000131629 7001_ $$aZhang, Li-Shu$$b1
000131629 7001_ $$aToombs, Jason$$b2
000131629 7001_ $$aKuo, Yi-Chun$$b3
000131629 7001_ $$aPiazza, John Tyler$$b4
000131629 7001_ $$aTuladhar, Rubina$$b5
000131629 7001_ $$aBarrett, Quinn$$b6
000131629 7001_ $$aFan, Chih-Wei$$b7
000131629 7001_ $$aZhang, Xuewu$$b8
000131629 7001_ $$aWalensky, Loren D$$b9
000131629 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b10$$udkfz
000131629 7001_ $$aCheng, Steven Y$$b11
000131629 7001_ $$00000-0003-2704-2377$$aBrekken, Rolf$$b12
000131629 7001_ $$aOpferman, Joseph T$$b13
000131629 7001_ $$aGreen, Douglas R$$b14
000131629 7001_ $$aMoldoveanu, Tudor$$b15
000131629 7001_ $$00000-0002-6119-0253$$aLum, Lawrence$$b16
000131629 773__ $$0PERI:(DE-600)1494945-3$$a10.1038/ncb3616$$gVol. 19, no. 10, p. 1226 - 1236$$n10$$p1226 - 1236$$tNature cell biology$$v19$$x1476-4679$$y2017
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