Osmotic Stress Resistance Imparts Acquired Anti-apoptotic Mechanisms in Lymphocytes
Osmotic Stress Resistance Imparts Acquired Anti-apoptotic Mechanisms in Lymphocytes
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DOI：
10.1074/jbc.m111.293001
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发表时间：
2012-02-24
影响因子：
4.8
通讯作者：
Cidlowski, John A.
中科院分区：
文献类型：
--
作者：
Bortner, Carl D.;Scoltock, Alyson B.;Cidlowski, John A.
细胞凋亡是一种随机的、生理性的细胞死亡形式，具有独特的形态和生化特性。在所有细胞中，细胞凋亡的一个显著特征是凋亡体积减少或AVD，它被认为是细胞死亡过程中的一个被动成分。大多数细胞具有固有的体积调节性增加(RVI)机制来对抗细胞大小的强加损失，然而T细胞是独特的，因为它们没有RVI反应。我们利用这一特性来探索RVI反应在细胞凋亡中的潜在调控作用。未成熟的T细胞暴露于高渗应激导致快速的、同步的和caspase依赖的细胞凋亡。多轮渗透胁迫后，细胞在正常培养液中的恢复导致了对渗透胁迫诱导的细胞凋亡具有抵抗力的细胞群的形成。这些细胞对通过内在细胞死亡途径激活的其他凋亡刺激也具有抵抗力，同时对外部凋亡刺激保持敏感。有趣的是，这些渗透胁迫抗性细胞没有表现出抗凋亡蛋白的增加，而是在暴露于内在的凋亡刺激后从线粒体中释放出细胞色素c。渗透胁迫抗性细胞产生了RVI反应，抑制RVI恢复了对凋亡剂的敏感性。对凋亡信号通路的分析表明，磷酸化AKT持续增加，它的抑制也阻止了导致细胞凋亡的RVI反应。这些结果定义了体积调节机制在细胞凋亡抵抗中的关键作用。
Apoptosis is a stochastic, physiological form of cell death that is characterized by unique morphological and biochemical properties. A defining feature of apoptosis in all cells is the apoptotic volume decrease or AVD, which has been considered a passive component of the cell death process. Most cells have inherent volume regulatory increase (RVI) mechanisms to contest an imposed loss in cell size, however T-cells are unique in that they do not have a RVI response. We utilized this property to explore potential regulatory roles of a RVI response in apoptosis. Exposure of immature T-cells to hyperosmotic stress resulted in a rapid, synchronous, and caspase-dependent apoptosis. Multiple rounds of osmotic stress followed by recovery of cells in normal media resulted in the development of a population of cells that were resistant to osmotic stress induced apoptosis. These cells were also resistant to other apoptotic stimuli that activate via the intrinsic cell death pathway, while remaining sensitive to extrinsic apoptotic stimuli. Interestingly, these osmotic stress resistant cells showed no increase in anti-apoptotic proteins, and released cytochrome c from their mitochondria following exposure to intrinsic apoptotic stimuli. The osmotic stress resistant cells developed a RVI response, and inhibition of the RVI restored sensitivity to apoptotic agents. Analysis of apoptotic signaling pathways showed a sustained increase in phospho-AKT, whose inhibition also prevented an RVI response resulting in apoptosis. These results define a critical role of volume regulation mechanisms in apoptotic resistance.