Hossini A M, Geilen C C, Fecker L F, Daniel P T, Eberle J
Department of Dermatology and Allergy, Skin cancer center, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin 12203, Germany.
Oncogene. 2006 Apr 6;25(15):2160-9. doi: 10.1038/sj.onc.1209253.
Pro- and antiapoptotic proteins of the large Bcl-2 family are critical regulators of apoptosis via the mitochondrial pathway. Whereas antiapoptotic proteins of the family share all four Bcl-2 homology domains (BH1-BH4), proapoptotic members may lack some of these domains, but all so far described proapoptotic Bcl-2 proteins enclose BH3. The bcl-x gene gives rise to several alternative splice products resulting in proteins with distinct functions as the antiapoptotic Bcl-xL and proapoptotic Bcl-xS. Here, we describe a novel Bcl-x splice product of 138 amino acids termed Bcl-xAK (Atypical Killer), which encloses the Bcl-2 homology domains BH2 and BH4 as well as the transmembrane domain, but lacks BH1 and BH3. Weak endogenous expression of Bcl-xAK was seen in melanoma and other tumor cells. Interestingly, its overexpression by applying a tetracycline-inducible expression system resulted in significant induction of apoptosis in melanoma cells, which occurred in synergism with drug-induced apoptosis. After exogenous overexpression, Bcl-xAK was localized both in mitochondrial and in cytosolic cell fractions. By these findings, a completely new class of Bcl-2-related proteins is introduced, which promotes apoptosis independently from the BH3 domain and implies additional, new mechanisms for apoptosis regulation in melanoma cells.
大型Bcl-2家族的促凋亡蛋白和抗凋亡蛋白是线粒体途径中凋亡的关键调节因子。该家族的抗凋亡蛋白共享所有四个Bcl-2同源结构域（BH1-BH4），而促凋亡成员可能缺少其中一些结构域，但迄今为止描述的所有促凋亡Bcl-2蛋白都包含BH3。bcl-x基因产生几种可变剪接产物，导致具有不同功能的蛋白，如抗凋亡的Bcl-xL和促凋亡的Bcl-xS。在这里，我们描述了一种新的138个氨基酸的Bcl-x剪接产物，称为Bcl-xAK（非典型杀手），它包含Bcl-2同源结构域BH2和BH4以及跨膜结构域，但缺少BH1和BH3。在黑色素瘤和其他肿瘤细胞中可见Bcl-xAK的内源性表达较弱。有趣的是，通过应用四环素诱导表达系统对其进行过表达，导致黑色素瘤细胞中凋亡显著诱导，这与药物诱导的凋亡协同发生。外源性过表达后，Bcl-xAK定位于线粒体和细胞溶质部分。通过这些发现，引入了一类全新的Bcl-2相关蛋白，其独立于BH3结构域促进凋亡，并暗示黑色素瘤细胞中凋亡调节的额外新机制。
