Korsmeyer S J
Division of Molecular Oncology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cancer Res. 1999 Apr 1;59(7 Suppl):1693s-1700s.
The BCL-2 gene was identified at the chromosomal breakpoint of t(14; 18)-bearing human follicular B cell lymphomas. BCL-2 proved to block programmed cell death rather than promote proliferation. Transgenic mice that overexpress Bcl-2 in the B cell lineage demonstrate extended cell survival and progress to high-grade lymphomas. Thus, BCL-2 initiated a new category of oncogenes, regulators of cell death. Bcl-2-deficient mice demonstrate fulminant apoptosis of lymphocytes, profound renal cell death and loss of melanocytes. BCL-2 protein duels with its counteracting twin, a partner known as BAX. When BAX is in excess, cells execute a death command; but, when BCL-2 dominates, the program is inhibited and cells survive. Bax-deficient mice display cellular hyperplasia, confirming its role as a proapoptotic molecule. An expanded family of BCL-2-related proteins shares homology clustered within four conserved regions termed BCL-2 homology 1 through 4 (BH1-4). These novel domains control the ability of these proteins to dimerize and function. An amphipathic alpha helix, BH3, is of particular importance for the proapoptotic family members. BID and BAD represent an evolving set of proapoptotic molecules, which bear sequence homology only at BH3. They appear to reside more proximal in the pathway serving as death ligands. BAD connects upstream signal transduction paths with the BCL-2 family, modulating this checkpoint for apoptosis. In the presence of survival factor interleukin-3, cells phosphorylate BAD on two serine residues. This inactivated BAD is held by the 14-3-3 protein, freeing BCL-XL and BCL-2 to promote survival. Activation of BAX results in the initiation of apoptosis. Downstream events in this program include mitochondrial dysfunction, as well as Caspase activation. The pro- and antiapoptotic BCL-2 family members represent central regulators in an evolutionarily conserved pathway of cell death. Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer.
BCL-2基因是在携带t(14;18)的人类滤泡性B细胞淋巴瘤的染色体断点处被鉴定出来的。事实证明，BCL-2可阻断程序性细胞死亡，而非促进细胞增殖。在B细胞谱系中过表达Bcl-2的转基因小鼠表现出细胞存活期延长，并发展为高级别淋巴瘤。因此，BCL-2开创了一类新的癌基因，即细胞死亡调节因子。Bcl-2基因缺陷型小鼠表现出淋巴细胞的暴发性凋亡、严重的肾细胞死亡和黑素细胞缺失。BCL-2蛋白与其拮抗蛋白、名为BAX的伙伴相互对抗。当BAX过量时，细胞执行死亡指令；但是，当BCL-2占主导时，该程序被抑制，细胞存活。Bax基因缺陷型小鼠表现出细胞增生，证实了其作为促凋亡分子的作用。一个扩展的BCL-2相关蛋白家族具有在四个称为BCL-2同源性1至4（BH1-4）的保守区域内聚集的同源性。这些新结构域控制这些蛋白二聚化和发挥功能的能力。一种两亲性α螺旋BH3对促凋亡家族成员尤为重要。BID和BAD代表一组不断演变的促凋亡分子，它们仅在BH3处具有序列同源性。它们似乎位于该途径中更靠近上游的位置，作为死亡配体。BAD将上游信号转导途径与BCL-2家族连接起来，调节这个细胞凋亡检查点。在存在生存因子白细胞介素-3的情况下，细胞在两个丝氨酸残基上使BAD磷酸化。这种失活的BAD被14-3-3蛋白结合，释放出BCL-XL和BCL-2以促进细胞存活。BAX的激活导致细胞凋亡的启动。该程序中的下游事件包括线粒体功能障碍以及半胱天冬酶激活。促凋亡和抗凋亡的BCL-2家族成员是细胞死亡进化保守途径中的核心调节因子。BCL-2家族的异常导致体内稳态紊乱，这是包括癌症在内的疾病中的一个致病事件。
