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首页> 外文期刊>Cellular Signalling >Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase
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Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase

机译：PP2A相关的p38丝裂原活化蛋白激酶对T细胞白血病细胞中的磷酸化酶2A（PP2A）抑制诱导的凋亡

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Serine/threonine phosphatase regulation of phosphorylation-mediated intracellular signaling controls a number of important processes in mammalian cells. In this study, we show that constitutively active protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase, is essential for T leukemia cell survival. Jurkat and CCRF-CEM T leukemia cells treated with the PP2A-selective inhibitor okadaic acid (OA) showed a dose- and time-dependent induction of apoptosis, as indicated by loss of mitochondrial transmembrane potential (Delta psi(m)), cleavage-induced activation of caspase-3, -8, and -9, and DNA fragmentation. In addition, caspase-8 or caspase-9 inhibition with z-IETD-fmk or z-LEHD-fmk, respectively, largely prevented OA-induced apoptosis. Although OA treatment did not affect constitutive Bcl-2 expression, overexpression of Bcl-2 prevented both OA-induced DNA fragmentation and dissipation of Delta psi(m). Furthermore, inhibition of caspase-3, -8, or -9 partially protected against OA-induced loss of Delta psi(m) In addition, caspase-9 and caspase-3 inhibition largely prevented procaspase-3 and procaspase-8 cleavage, respectively, while caspase-8 inhibition partially interfered with procaspase-9 cleavage in OA-treated T leukemia cells. Thus, PP2A inhibition triggered the intrinsic pathway of apoptosis, which was enhanced by a mitochondrial feedback amplification loop. PP2A has also been implicated in the regulation of p38 mitogen-activated protein kinase (MAPK). Co-immunoprecipitation analysis revealed a physical association between the catalytic subunit of PP2A and p38 MAPK in T leukemia cells. Moreover, OA treatment caused p38 MAPK to be phosphorylated in a dose- and time-dependent fashion, indicating that PP2A prevented p38 MAPK activation. Although p38 MAPK activation usually promotes apoptosis, pharmacologic inhibition of p38 MAPK exacerbated OA-induced DNA fragmentation and loss of Delta psi m in T leukemia cells, suggesting that, in this instance, the p38 MAPK signaling pathway promoted cell survival. Collectively, these findings indicate that PP2A and p38 MAPK have coordinate effects on signaling pathways that regulate the survival of T leukemia cells. (c) 2006 Elsevier Inc. All rights reserved.
机译：磷酸化介导的细胞内信号转导的丝氨酸/苏氨酸磷酸酶调节控制了哺乳动物细胞中的许多重要过程。在这项研究中，我们表明组成性活性蛋白磷酸酶2A（PP2A）是丝氨酸/苏氨酸磷酸酶，对于T白血病细胞的生存至关重要。用PP2A选择性抑制剂冈田酸（OA）处理的Jurkat和CCRF-CEM T白血病细胞显示出剂量依赖性和时间依赖性的凋亡诱导，如线粒体跨膜电位的丧失（Δpsi（m）），裂解-诱导caspase-3，-8和-9的活化以及DNA断裂。此外，分别用z-IETD-fmk或z-LEHD-fmk抑制caspase-8或caspase-9可以很大程度上防止OA诱导的细胞凋亡。尽管OA处理不会影响Bcl-2的组成性表达，但Bcl-2的过表达可以阻止OA诱导的DNA片段化和Delta psi（m）的耗散。此外，对caspase-3，-8或-9的抑制可部分抵抗OA引起的Delta psi（m）损失。此外，对caspase-9和caspase-3的抑制分别分别阻止了procaspase-3和procaspase-8的裂解。 ，而caspase-8抑制在OA处理的T白血病细胞中部分干扰了procaspase-9的裂解。因此，PP2A抑制触发了细胞凋亡的内在途径，这是由线粒体反馈放大环增强的。 PP2A也参与了p38丝裂原活化蛋白激酶（MAPK）的调控。免疫共沉淀分析显示T白血病细胞中PP2A的催化亚基与p38 MAPK之间存在物理联系。此外，OA处理导致p38 MAPK呈剂量和时间依赖性磷酸化，表明PP2A阻止了p38 MAPK活化。尽管p38 MAPK激活通常促进细胞凋亡，但是p38 MAPK的药理抑制作用加剧了OA诱导的T白血病细胞中的DNA片段化和Delta psi m的丢失，这表明在这种情况下，p38 MAPK信号传导途径促进了细胞存活。总体而言，这些发现表明PP2A和p38 MAPK对调节T白血病细胞存活的信号通路具有协同作用。 （c）2006 Elsevier Inc.保留所有权利。

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