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An Spl transcription factor coordinates caspase- dependent and -independent apoptotic pathways

机译：Spl转录因子协调caspase依赖性和非依赖性凋亡途径

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摘要

During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways~(1,2). Although the mechanisms of caspase-dependent and -independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the Caenorhabditis elegans Spl transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells-the sisters of the pharyngeal M4 motor neuron and the AQR sensory neuron-by transcriptionally activating both caspase-dependent and -independent apoptotic pathways. SPTF-3 directly drives the transcription of the gene egl-1, which encodes a BH3-only protein that promotes apoptosis through the activation of the CED-3 caspase~3. In addition, SPTF-3 directly drives the transcription of the AMP- activated protein kinase-related gene pig-1, which encodes a protein kinase and functions in apoptosis of the M4 sister and AQR sister independently of the pathway that activates CED-3 (refs 4,5). Thus, a single transcription factor controls two distinct cell-killing programs that act in parallel to drive apoptosis. Our findings reveal a bivalent regulatory node for caspase-dependent and -independent pathways in the regulation of cell-type-specific apoptosis. We propose that such nodes might act as features of a general mechanism for regulating cell-type-specific apoptosis and could be therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.
机译：在动物发育过程中，对细胞凋亡的适当调节需要细胞死亡程序的精确时空执行，该程序可以包括caspase依赖性和caspase依赖性途径[1,2]。尽管已经广泛研究了胱天蛋白酶依赖性和非依赖性细胞杀伤的机制，但是尚不清楚这些途径如何在注定要死亡的单个细胞内协调。在这里，我们显示秀丽隐杆线虫Spl转录因子SPTF-3通过转录激活胱天蛋白酶依赖性和非依赖性凋亡途径来指定至少两个细胞（咽M4运动神经元和AQR感觉神经元的姐妹）的程序性细胞死亡。 。 SPTF-3直接驱动基因egl-1的转录，该基因编码仅BH3的蛋白质，该蛋白质通过激活CED-3 caspase〜3促进细胞凋亡。此外，SPTF-3直接驱动AMP激活的蛋白激酶相关基因Pig-1的转录，该基因编码蛋白激酶，并独立于激活CED-3的途径在M4姐妹和AQR姐妹的细胞凋亡中起作用（参考文献4,5）。因此，单个转录因子控制两个不同的细胞杀伤程序，这些程序并行作用以驱动凋亡。我们的发现揭示了在细胞类型特异性凋亡调控中半胱天冬酶依赖性和非依赖性途径的二价调控节点。我们建议这种节点可能充当调节细胞类型特异性细胞凋亡的一般机制的特征，并可能成为涉及通过多种细胞杀伤机制引起细胞凋亡失调的疾病的治疗靶点。

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  • 来源
    《Nature》 |2013年第7462期|354-358|共5页
  • 作者

    Takashi Hirose; H. Robert Horvitz;

  • 作者单位

    Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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