当前位置: X-MOL 学术Nat. Cell Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor
Nature Cell Biology ( IF 17.3 ) Pub Date : 2017-09-25 00:00:00 , DOI: 10.1038/ncb3616
Xiaofeng Wu , Li-shu Zhang , Jason Toombs , Yi-Chun Kuo , John Tyler Piazza , Rubina Tuladhar , Quinn Barrett , Chih-wei Fan , Xuewu Zhang , Loren D. Walensky , Marcel Kool , Steven Y. Cheng , Rolf Brekken , Joseph T. Opferman , Douglas R. Green , Tudor Moldoveanu , Lawrence Lum

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.

中文翻译:

线粒体生存前期BCL-2蛋白通过抑制SUFU肿瘤抑制因子来调节基因转录

促凋亡和抗凋亡BCL-2家族成员之间的直接相互作用形成了线粒体外膜(OMM)做出细胞死亡决策的基础。在这里我们报告说,发现三种抗凋亡的BCL-2蛋白(MCL-1,BCL-2和BCL-XL)不受OMM的束缚,可作为生存和生长程序的转录调节因子。抗凋亡的BCL-2蛋白与SUFU(融合的抑制物)中发现的BCL-2同源性(BH)域序列结合,SUFU是GLI DNA结合蛋白的肿瘤抑制物和拮抗剂。BCL-2蛋白直接促进SUFU转换,抑制SUFU-GLI相互作用,并诱导GLI目标基因BCL-2,MCL-1和BCL-XL的表达。抗凋亡BCL-2蛋白/ SUFU前馈信号可促进癌细胞存活和生长,并可以用BH3模拟物(靶向抗凋亡BCL-2蛋白的小分子)禁用。我们的发现描绘了一种在GLI相关肿瘤中抵抗药物耐药性的化学策略,并揭示了BCL-2蛋白作为转录调节因子的意想不到的功能。
更新日期:2017-09-30
down
wechat
bug