Apoptotic threshold is lowered by p53 transactivation of caspase-6

Little is known about how a cell's apoptotic threshold is controlled after exposure to chemotherapy, although the p53 tumor suppressor has been implicated. We identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. A p53-dependent increase in procaspase-6 protein level allows for an increase in caspase-6 activity and caspase-6-specific Lamin A cleavage in response to Adriamycin exposure. Specific inhibition of caspase-6 blocks cell death in a manner that correlates with caspase-6 mRNA induction by p53 and enhances long-term survival in response to a p53-mediated apoptotic signal. Caspase-6 is an executioner caspase found directly regulated by p53, and the most downstream component of the death pathway controlled by p53. The induction of caspase-6 expression lowers the cell death threshold in response to apoptotic signals that activate caspase-6. Our results provide a potential mechanism of lowering the death threshold, which could be important for chemosensitization.

尽管已有研究证实p53肿瘤抑制因子（p53 tumor suppressor）参与其中，但目前学界对细胞经化疗处理后其凋亡阈值（apoptotic threshold）的调控机制仍不甚明晰。本研究将执行型半胱天冬酶-6（executioner caspase-6）鉴定为p53的转录靶标，其调控机制为：p53通过DNA结合（DNA binding）作用结合至半胱天冬酶-6基因的第三内含子（intron），并介导反式激活（transactivation）。p53依赖性的半胱天冬酶-6酶原（procaspase-6）蛋白水平上调，可使细胞在阿霉素（Adriamycin）刺激下，半胱天冬酶-6活性升高并发生半胱天冬酶-6特异性的核纤层蛋白A（Lamin A）切割。对执行型半胱天冬酶-6的特异性抑制可阻断细胞死亡，该效应与p53介导的半胱天冬酶-6 mRNA诱导呈正相关，且可增强细胞在p53介导的凋亡信号刺激下的长期存活率。执行型半胱天冬酶-6是首个被证实受p53直接调控的执行型半胱天冬酶，亦是p53介导的细胞死亡通路中最下游的效应组分。半胱天冬酶-6表达的诱导可降低细胞响应激活半胱天冬酶-6的凋亡信号时的死亡阈值。本研究结果为降低细胞死亡阈值提供了潜在机制，该机制或对化疗增敏（chemosensitization）具有重要意义。