Haupt Susan, Berger Michael, Goldberg Zehavit, Haupt Ygal
Department of Pharmacy, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. doi: 10.1242/jcs.00739.
Exposure to cellular stress can trigger the p53 tumor suppressor, a sequence-specific transcription factor, to induce cell growth arrest or apoptosis. The choice between these cellular responses is influenced by many factors, including the type of cell and stress, and the action of p53 co-activators. p53 stimulates a wide network of signals that act through two major apoptotic pathways. The extrinsic, death receptor pathway triggers the activation of a caspase cascade, and the intrinsic, mitochondrial pathway shifts the balance in the Bcl-2 family towards the pro-apoptotic members, promoting the formation of the apoptosome, and consequently caspase-mediated apoptosis. The impact of these two apoptotic pathways may be enhanced when they converge through Bid, which is a p53 target. The majority of these apoptotic effects are mediated through the induction of specific apoptotic target genes. However, p53 can also promote apoptosis by a transcription-independent mechanism under certain conditions. Thus, a multitude of mechanisms are employed by p53 to ensure efficient induction of apoptosis in a stage-, tissue- and stress-signal-specific manner. Manipulation of the apoptotic functions of p53 constitutes an attractive target for cancer therapy.
暴露于细胞应激可触发p53肿瘤抑制因子（一种序列特异性转录因子）诱导细胞生长停滞或凋亡。这些细胞反应之间的选择受多种因素影响，包括细胞类型和应激类型以及p53共激活因子的作用。p53刺激通过两条主要凋亡途径起作用的广泛信号网络。外在的死亡受体途径触发半胱天冬酶级联反应的激活，内在的线粒体途径使Bcl-2家族的平衡向促凋亡成员倾斜，促进凋亡小体的形成，从而导致半胱天冬酶介导的凋亡。当这两条凋亡途径通过p53靶标Bid汇聚时，它们的影响可能会增强。这些凋亡效应大多数是通过诱导特定的凋亡靶基因介导的。然而，在某些情况下，p53也可以通过转录非依赖机制促进凋亡。因此，p53采用多种机制以阶段、组织和应激信号特异性方式确保有效诱导凋亡。对p53凋亡功能的操控构成癌症治疗的一个有吸引力的靶点。
