Wu Xiaofeng, Zhang Li-Shu, Toombs Jason, Kuo Yi-Chun, Piazza John Tyler, Tuladhar Rubina, Barrett Quinn, Fan Chih-Wei, Zhang Xuewu, Walensky Loren D, Kool Marcel, Cheng Steven Y, Brekken Rolf, Opferman Joseph T, Green Douglas R, Moldoveanu Tudor, Lum Lawrence
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nat Cell Biol. 2017 Oct;19(10):1226-1236. doi: 10.1038/ncb3616. Epub 2017 Sep 25.
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.
促凋亡和抗凋亡BCL-2家族成员之间的直接相互作用构成了线粒体外膜（OMM）处细胞死亡决策的基础。在此，我们报告发现三种未与OMM相连的抗凋亡BCL-2蛋白（MCL-1、BCL-2和BCL-XL）作为一种促生存和生长程序的转录调节因子发挥作用。抗凋亡BCL-2蛋白与在SUFU（融合抑制因子）中发现的一种BCL-2同源（BH）结构域序列结合，SUFU是一种肿瘤抑制因子，也是GLI DNA结合蛋白的拮抗剂。BCL-2蛋白直接促进SUFU的周转，抑制SUFU与GLI的相互作用，并诱导GLI靶基因BCL-2、MCL-1和BCL-XL的表达。抗凋亡BCL-2蛋白/SUFU前馈信号促进癌细胞的存活和生长，并且可以被BH3模拟物——靶向抗凋亡BCL-2蛋白的小分子所阻断。我们的研究结果描绘了一种对抗GLI相关肿瘤耐药性的化学策略，并揭示了BCL-2蛋白作为转录调节因子的意外功能。
