González-García M, Pérez-Ballestero R, Ding L, Duan L, Boise L H, Thompson C B, Núñez G
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Development. 1994 Oct;120(10):3033-42. doi: 10.1242/dev.120.10.3033.
Most examples of cell death in animals are controlled by a genetic program that is activated within the dying cell. The apoptotic process is further regulated by a set of genes that act as repressors of cell death. Of these, bcl-2 is expressed in a variety of embryonic and postnatal tissues which suggests a critical role for bcl-2 in organogenesis and tissue homeostasis. Surprisingly, mutant mice with targeted disruption of bcl-2 appear normal at birth and complete maturation of lymphoid tissues before succumbing to fulminant lymphopenia and polycystic renal disease by 2-5 weeks of age. This suggests that there may be genes other than bcl-2 that can regulate apoptosis during development. To begin to investigate this possibility, we have cloned and characterized the murine bcl-x gene, whose human counterpart displays striking homology to bcl-2. The predicted murine bcl-xL gene product exhibits a high level of amino acid identity (97%) to its human counterpart. Just like Bcl-2, the murine bcl-xL gene product can act as a dominant inhibitor of cell death upon growth factor withdrawal. In addition, the bulk of the bcl-xL product localizes to the periphery of mitochondria as assessed by a bcl-xL-tag expression system, suggesting that both Bcl-2 and Bcl-xL proteins prevent cell death by a similar mechanism. bcl-xL is the most abundant bcl-x mRNA species expressed in embryonic and adult tissues. The levels of bcl-xL mRNA appear higher than those of bcl-2 during embryonal development and in several adult organs including bone marrow, brain, kidney and thymus. In addition to bcl-xL, we have identified another form of bcl-x mRNA, bcl-x beta, that results from an unspliced bcl-x transcript. bcl-x beta mRNA is expressed in various embryonic and postnatal tissues. Surprisingly, the expression of bcl-xS (a negative regulator of programmed cell death) was undetectable by a sensitive S1-nuclease assay and polymerase chain reaction analysis of mouse tissues. Based on its tissue and developmental patterns of expression, it appears that bcl-x may play an important role in the regulation of cell death during development and tissue homeostasis.
动物体内大多数细胞死亡的例子是由死亡细胞内激活的遗传程序控制的。凋亡过程还受到一组作为细胞死亡抑制因子的基因的进一步调控。其中，bcl-2在多种胚胎和出生后组织中表达，这表明bcl-2在器官发生和组织稳态中起关键作用。令人惊讶的是，bcl-2基因靶向破坏的突变小鼠出生时看似正常，并在2至5周龄时死于暴发性淋巴细胞减少症和多囊性肾病之前，淋巴组织完全成熟。这表明可能存在除bcl-2之外的其他基因，它们可以在发育过程中调节细胞凋亡。为了开始研究这种可能性，我们克隆并鉴定了小鼠bcl-x基因，其人类对应物与bcl-2具有显著的同源性。预测的小鼠bcl-xL基因产物与其人类对应物具有高水平的氨基酸同一性（97%）。与Bcl-2一样，小鼠bcl-xL基因产物在生长因子撤除后可作为细胞死亡的显性抑制剂。此外，通过bcl-xL标签表达系统评估，大部分bcl-xL产物定位于线粒体周边，这表明Bcl-2和Bcl-xL蛋白通过类似机制防止细胞死亡。bcl-xL是在胚胎和成年组织中表达最丰富的bcl-x mRNA种类。在胚胎发育期间以及包括骨髓、脑、肾和胸腺在内的几个成年器官中，bcl-xL mRNA的水平似乎高于bcl-2。除了bcl-xL，我们还鉴定了另一种bcl-x mRNA形式，即bcl-xβ，它来自未剪接的bcl-x转录本。bcl-xβ mRNA在各种胚胎和出生后组织中表达。令人惊讶的是，通过对小鼠组织进行敏感的S1核酸酶分析和聚合酶链反应分析，未检测到bcl-xS（程序性细胞死亡的负调节因子）的表达。基于其组织和发育表达模式，bcl-x似乎在发育和组织稳态过程中细胞死亡的调节中起重要作用。
