Kratz E, Eimon P M, Mukhyala K, Stern H, Zha J, Strasser A, Hart R, Ashkenazi A
Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080, USA.
Cell Death Differ. 2006 Oct;13(10):1631-40. doi: 10.1038/sj.cdd.4402016. Epub 2006 Aug 4.
Members of the Bcl-2 protein family control the intrinsic apoptosis pathway. To evaluate the importance of this family in vertebrate development, we investigated it in the zebrafish (Danio rerio). We found that the zebrafish genome encodes structural and functional homologs of most mammalian Bcl-2 family members, including multi-Bcl-2-homology (BH) domain proteins and BH3-only proteins. Apoptosis induction by gamma-irradiation required zBax1 and zPuma, and could be prevented by overexpression of homologs of prosurvival Bcl-2 family members. Surprisingly, zebrafish Bax2 (zBax2) was homologous to mammalian Bax by sequence and synteny, yet demonstrated functional conservation with human Bak. Morpholino knockdown of both zMcl-1a and zMcl-1b revealed their critical role in early embryonic zebrafish development, and in the modulation of apoptosis activation through the extrinsic pathway. These data indicate substantial functional similarity between zebrafish and mammalian Bcl-2 family members, and establish the zebrafish as a relevant model for studying the intrinsic apoptosis pathway.
Bcl-2蛋白家族成员控制着内源性凋亡途径。为了评估该家族在脊椎动物发育中的重要性，我们在斑马鱼（Danio rerio）中对其进行了研究。我们发现斑马鱼基因组编码了大多数哺乳动物Bcl-2家族成员的结构和功能同源物，包括多Bcl-2同源（BH）结构域蛋白和仅含BH3结构域的蛋白。γ射线诱导的凋亡需要zBax1和zPuma，并且可以通过过表达促生存Bcl-2家族成员的同源物来预防。令人惊讶的是，斑马鱼Bax2（zBax2）在序列和同线性上与哺乳动物Bax同源，但在功能上与人类Bak保守。对zMcl-1a和zMcl-1b进行吗啉代敲低揭示了它们在斑马鱼早期胚胎发育以及通过外源性途径调节凋亡激活中的关键作用。这些数据表明斑马鱼和哺乳动物Bcl-2家族成员之间存在实质性的功能相似性，并确立了斑马鱼作为研究内源性凋亡途径的相关模型。
