Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance
Regulation of apoptosis by bcl-2 family proteins and its role in cancer and chemoresistance
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DOI：
10.1097/00001622-199511000-00012
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发表时间：
1995-01-01
影响因子：
3.4
通讯作者：
Reed, John C.
中科院分区：
文献类型：
--
作者：
Reed, John C.
在基本上所有具有自我更新能力的组织中，有丝分裂产生的细胞产生和程序性细胞死亡（PCD）导致的细胞损失之间存在着微妙的平衡，这种平衡将细胞总数维持在生理上适当的范围内。在人类肿瘤细胞中经常发生的基因改变，要么是细胞分裂过程失调，导致细胞增殖更快，要么是影响生理细胞死亡机制，导致细胞损失速度减慢，并有助于癌细胞在体内的克隆扩增。PCD是一种活跃的细胞自杀形式，有时需要新的基因表达来启动，在许多情况下，但不是所有的情况下，在一系列生化和形态事件中达到高潮。这些包括基因组DNA被核酸内切酶切割、染色质缩聚（固缩）、核断裂、细胞骨架和其他蛋白质的蛋白质水解、质膜起泡和细胞收缩。在许多方面，这些生化事件可以被视为细胞自消化的一种形式，在这种形式中，细胞的大分子成分被降解，以便它们的组成亚基可以在体内循环。当以经典形式出现时，伴随这种类型细胞死亡的形态学事件被广泛地称为细胞凋亡。尽管PCD通路因其在维持组织稳态的正常生理细胞死亡机制中的作用而广为人知，但多种病理条件和外部因素均可触发PCD通路。在这些细胞凋亡刺激因素中，基本上包括所有化疗药物和放疗，这一发现与我们理解目前可用的癌症治疗方法如何起作用以及制定改进它们的策略具有相当大的相关性。在这篇综述中，讨论了bcl-2蛋白家族成员对PCD的调控，主要是在人类癌症的背景下，BCL2家族基因的异常表达经常发生，并导致癌症的起源和我们治疗癌症的困难。
In essentially all tissues that have self-renewal capacity, there exists a delicate balance between cell production by mitogenesis and cell loss due to programmed cell death (PCD), which maintains total cell numbers within physiologically appropriate ranges. Genetic alterations that either dysregulate the cell division process, resulting in faster cell proliferation, or that affect physiological cell death mechanisms that cause slower rates of cell loss, occur frequently in human tumor cells and contribute to the clonal expansion of cancer cells in vivo. PCD is an active form of cell suicide that sometimes requires new gene expression for its initiation and that in many, but not all, cases culminates in a characteristic set of biochemical and morphological events. These include genomic DNA cleavage by endonucleases, chromatin condensation (pyknosis), nuclear fragmentation, proteolysis of cytoskeletal and other proteins, plasma membrane blebbing, and cell shrinkage. In many ways, these biochemical events can be viewed as a form of cellular autodigestion in which the macromolecular components of cells are degraded so that their constituent subunits can be recycled in the body. When present in their classical form, the morphological events accompanying this type of cell death are broadly termed apoptosis. Though well known for its role in the normal physiological cell death mechanisms that maintain tissue homeostasis, a wide variety of pathological conditions and external factors can trigger the PCD pathway. Included among these apoptotic stimuli are essentially all chemotherapeutic drugs and radiation, a finding of considerable relevance to our understanding of how currently available treatments of cancer work and for devising strategies for improving them. In this review, the regulation of PCD by members of the bcl-2 family of proteins is discussed, primarily within the context of human cancers where abnormalities in the expression of BCL2 family genes frequently occur and contribute both to the origins of cancer and our difficulty in treating it.