Maurer Carine W, Chiorazzi Michael, Shaham Shai
Laboratory of Developmental Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Development. 2007 Apr;134(7):1357-68. doi: 10.1242/dev.02818. Epub 2007 Feb 28.
Temporal control of programmed cell death is necessary to ensure that cells die at only the right time during animal development. How such temporal regulation is achieved remains poorly understood. In some Caenorhabditis elegans somatic cells, transcription of the egl-1/BH3-only gene promotes cell-specific death. The EGL-1 protein inhibits the CED-9/Bcl-2 protein, resulting in the release of the caspase activator CED-4/Apaf-1. Subsequent activation of the CED-3 caspase by CED-4 leads to cell death. Despite the important role of egl-1 transcription in promoting CED-3 activity in cells destined to die, it remains unclear whether the temporal control of cell death is mediated by egl-1 expression. Here, we show that egl-1 and ced-9 play only minor roles in the death of the C. elegans tail-spike cell, demonstrating that temporal control of tail-spike cell death can be achieved in the absence of egl-1. We go on to show that the timing of the onset of tail-spike cell death is controlled by transcriptional induction of the ced-3 caspase. We characterized the developmental expression pattern of ced-3, and show that, in the tail-spike cell, ced-3 expression is induced shortly before the cell dies, and this induction is sufficient to promote the demise of the cell. Both ced-3 expression and cell death are dependent on the transcription factor PAL-1, the C. elegans homolog of the mammalian tumor suppressor gene Cdx2. PAL-1 can bind to the ced-3 promoter sites that are crucial for tail-spike cell death, suggesting that it promotes cell death by directly activating ced-3 transcription. Our results highlight a role that has not been described previously for the transcriptional regulation of caspases in controlling the timing of cell death onset during animal development.
程序性细胞死亡的时间控制对于确保细胞仅在动物发育的正确时间死亡是必要的。然而，目前对于这种时间调控是如何实现的仍知之甚少。在秀丽隐杆线虫的一些体细胞中，仅含BH3结构域的egl-1基因的转录促进细胞特异性死亡。EGL-1蛋白抑制CED-9/Bcl-2蛋白，从而导致半胱天冬酶激活剂CED-4/Apaf-1的释放。随后，CED-4对CED-3半胱天冬酶的激活导致细胞死亡。尽管egl-1转录在促进注定死亡的细胞中CED-3活性方面发挥着重要作用，但细胞死亡的时间控制是否由egl-1表达介导仍不清楚。在这里，我们表明egl-1和ced-9在秀丽隐杆线虫尾尖细胞的死亡中仅起次要作用，这表明在没有egl-1的情况下也可以实现尾尖细胞死亡的时间控制。我们进一步表明，尾尖细胞死亡开始的时间是由ced-3半胱天冬酶的转录诱导所控制的。我们对ced-3的发育表达模式进行了表征，并表明，在尾尖细胞中，ced-3表达在细胞死亡前不久被诱导，并且这种诱导足以促进细胞死亡。ced-3表达和细胞死亡都依赖于转录因子PAL-1，它是哺乳动物肿瘤抑制基因Cdx2的秀丽隐杆线虫同源物。PAL-1可以结合对尾尖细胞死亡至关重要的ced-3启动子位点，这表明它通过直接激活ced-3转录来促进细胞死亡。我们的结果突出了半胱天冬酶转录调控在动物发育过程中控制细胞死亡开始时间方面的一个此前未被描述的作用。
