Reed J C
Burnham Institute, La Jolla, CA 92037, USA.
Behring Inst Mitt. 1996 Oct(97):72-100.
The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. The gene encoding this protein was first discovered because of its involvement in the t(14;18) chromosomal translocations commonly found in B-cell lymphomas, where it contributes to neoplastic cell expansion by preventing cell turnover due to programmed cell death. Overexpression of BCL-2 also occurs in many other types of human tumors, including cancers of the prostate, colon, and lung, and has been associated with chemoresistance and radioresistance in some types of malignancy. Conversely, expression of BCL-2 is frequently reduced in the circulating lymphocytes of persons infected with Human Immunodeficiency Virus (HIV), which are prone to apoptotic cell death. Since the discovery of Bcl-2 a decade ago, several other cellular and viral genes encoding homologous proteins have been identified, some of which suppress cell death akin to Bcl-2 (Bcl-XL, Mcl-1, A1/Bfl-1, Nr13, Ced-9, BHRF-1) and others which promote apoptosis (Bax, Bcl-Xs, Bak, Bik, Bad). Several of these Bcl-2 family proteins are capable of physically interacting with each other through a complex network of homo- and heterodimers. The expression of some of these other BCL-2 family genes becomes altered in human cancers, as well as in the setting of ischemia and some other pathological conditions, suggesting a potentially important role for these Bcl-2 homologs in human diseases characterized by either insufficient or excessive cell death. Despite intensive investigation, the mechanisms by which Bcl-2 and its homologs control cell life and death largely remain enigmatic. Knowledge about the specific domains in Bcl-2 family proteins that are required for interactions with other proteins and for function however is beginning to provide insights into the molecular mechanisms through which these proteins regulate the programmed cell death pathway in normalcy and disease.
Bcl-2蛋白可阻断程序性细胞死亡和凋亡这一进化保守途径中的一个远端步骤。编码该蛋白的基因最初是因其参与常见于B细胞淋巴瘤的t(14;18)染色体易位而被发现的，在这种情况下，它通过阻止程序性细胞死亡导致的细胞更新来促进肿瘤细胞的增殖。BCL-2在许多其他类型的人类肿瘤中也存在过表达，包括前列腺癌、结肠癌和肺癌，并且在某些类型的恶性肿瘤中与化疗耐药性和放疗耐受性有关。相反，感染人类免疫缺陷病毒（HIV）的人的循环淋巴细胞中BCL-2的表达常常降低，这些淋巴细胞易于发生凋亡性细胞死亡。自十年前发现Bcl-2以来，已经鉴定出其他几个编码同源蛋白的细胞和病毒基因，其中一些类似于Bcl-2抑制细胞死亡（Bcl-XL、Mcl-1、A1/Bfl-1、Nr13、Ced-9、BHRF-1），而其他一些则促进凋亡（Bax、Bcl-Xs、Bak、Bik、Bad）。这些Bcl-2家族蛋白中的几种能够通过同型和异型二聚体的复杂网络相互进行物理相互作用。这些其他BCL-2家族基因中的一些在人类癌症以及缺血和其他一些病理情况下表达会发生改变，这表明这些Bcl-2同源物在以细胞死亡不足或过度为特征的人类疾病中可能发挥重要作用。尽管进行了深入研究，但Bcl-2及其同源物控制细胞生死的机制在很大程度上仍然是个谜。然而，关于Bcl-2家族蛋白中与其他蛋白相互作用及发挥功能所需的特定结构域的知识，正开始为这些蛋白在正常和疾病状态下调节程序性细胞死亡途径的分子机制提供见解。
