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首页> 外文期刊>Advances in enzyme regulation >Potassium is a critical regulator of apoptotic enzymes in vitro and in vivo.
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Potassium is a critical regulator of apoptotic enzymes in vitro and in vivo.

机译：钾是体外和体内凋亡酶的关键调节剂。

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Apoptosis, or programmed cell death, is a fundamental biological process involved in many physiological and pathological phenomena. This process is predominantly catabolic in which cellular macromolecules are broken down by distinct enzymes to be later recycled in healthy cells. These enzymes are arranged in an elaborate cascade that serves to both propagate and amplify a death signal as well as process bulk macromolecules and inhibit repair systems. One of the best-characterized enzyme systems involved in apoptosis is the activation of a nuclease(s) that degrades the genome into discrete oligonucleosomal fragments, clearly committing a cell to death. Using two different in vitro models, we have shown that K+ directly inhibits this/these nuclease(s) with complete inhibition observed at cellular concentrations of K+ found in non-dying cells (150 mM). These data suggest that K+ concentrations in living cells suppress apoptotic nuclease activity. One of the nucleases involved in apoptotic DNA degradation (NUC18/Cyclophilin) has been purified in our laboratory and found to be inhibited by similar concentrations of K+. Upstream of DNA fragmentation a specific class of proteases, termed caspases, are activated which propagate an apoptotic signal and lead to downstream events such as DNA fragmentation. Using an in vitro model of caspase activation, we also observed that activation of this enzyme is also completely inhibited by normal physiological K+ levels, suggesting that K+ levels in non-dying cells suppress multiple portions of the apoptotic enzyme cascade. These results suggest that K+ concentrations may decrease in cells undergoing apoptosis and both physical and fluorescence techniques document an intracellular K+ concentration of 35 mM in apoptotic cells. This loss of K+ also accounts for changes in cell volume (cell shrinkage) that are universally associated with apoptosis. Measurements of K+ concentration in shrunken and non-shrunken cells demonstrated that only shrunken cells contain a reduced concentration of intracellular K+. Importantly, both the nuclease and caspase activity were found exclusively in this shrunken population providing an absolute correlation between the activity of these enzymes and low K+ levels within a cell. Finally, suppressing K+ efflux in whole cells prevents the activation of these enzymes whereas enhancing the efflux of this ion facilitates enzymatic activity. These results suggest a direct cause and effect relationship between the level of K+ and the activity of apoptotic enzymes. Taken together we have shown a critical and novel mechanism that regulates apoptosis by a direct effect on the apoptotic enzymes.
机译：凋亡或程序性细胞死亡是涉及许多生理和病理现象的基本生物学过程。这个过程主要是分解代谢，其中细胞大分子被不同的酶分解，然后在健康细胞中再循环。这些酶以精细的级联排列，既可传播和放大死亡信号，又可处理大分子并抑制修复系统。参与凋亡的最典型的酶系统之一是核酸酶的激活，该酶将基因组降解为离散的寡核小体片段，显然使细胞死亡。使用两种不同的体外模型，我们显示K +直接抑制这种/这些核酸酶，并且在非濒死细胞（150 mM）中发现的K +细胞浓度下具有完全抑制作用。这些数据表明活细胞中的K +浓度会抑制凋亡核酸酶的活性。在我们的实验室中已经纯化了一种参与凋亡性DNA降解的核酸酶（NUC18 / Cyclophilin），并被类似浓度的K +抑制。 DNA片段的上游激活称为胱天蛋白酶的一类特殊蛋白酶，该蛋白酶传播凋亡信号并导致下游事件，例如DNA片段化。使用半胱天冬酶激活的体外模型，我们还观察到该酶的激活也被正常的生理K +水平完全抑制，这表明非染色细胞中的K +水平抑制了凋亡酶级联反应的多个部分。这些结果表明，在经历凋亡的细胞中K +浓度可能降低，物理和荧光技术均证明凋亡细胞中细胞内K +浓度为35 mM。 K +的这种丧失还解释了与凋亡普遍相关的细胞体积变化（细胞收缩）。收缩细胞和非收缩细胞中K +浓度的测量结果表明，只有收缩细胞的细胞内K +浓度降低。重要的是，核酸酶和半胱天冬酶的活性仅在这个缩小的种群中发现，提供了这些酶的活性与细胞内低K +水平之间的绝对相关性。最后，抑制全细胞中的K +流出阻止了这些酶的激活，而增强该离子的流出则促进了酶的活性。这些结果表明K +的水平与凋亡酶的活性之间存在直接的因果关系。综上所述，我们已经显示出通过直接作用于凋亡酶来调节细胞凋亡的关键和新颖机制。

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