Roles of a new signal transducing enzyme, phospholipase D (PLD) during cellular apoptosis

新型信号转导酶磷脂酶 D (PLD) 在细胞凋亡过程中的作用

基本信息

批准号：
10670136
负责人：
NAKASHIMA Shigeru
金额：
$ 2.37万
依托单位：
Gifu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670136/
关键词：
phospholipase D apoptosis differentiation PLD1 PLDOA protein tyrosine kinase ceramide oxygen stress 酸化ストレス MAPキナーゼ酵素ストレス

项目摘要

Phospholipase D (PLD) hydrolyzes phospholipids, especially phosphatidylcholine (PC) to phosphatidic acid (PA) and choline. PA acts as a second messenger and can be converted to other messenger molecules, such as lysophosphatidic acid (LPA) and 1,2-diacylglycerol (DG). Recent cDNA cloning studies have revealed the existence of at least two isozymes (PLD1, PLD2) in mammalian cells. For PLD1, two alternatively spliced forms, PLD1a and PLD1b have been identified. In addition to these, another type of PLD (PLDOA) which is activated by unsaturated fatty acids such as oleic acid has been suggested, although its molecular nature is not known yet. In addition to glycerophospholipids, sphingomyelin hydrolysis is induced by a variety of stress signals including cytokines and chemotheraputic agents. Hydrolysis of sphingomyelin by sphingomyelinase results in the production of ceramide, which is regarded as a second messenger of differentiation and apoptosis. N-acetylsphingosine (CィイD22ィエD2-ceramide … More ), a membrane-permeable analogue, inhibits PLD activity in several types of cells, including RBL-2H3 cells, PC12 cells and C6 glioma cells. During apoptotic process of these cells, GTPγS-dependent PLD activity in cell lysates decreased time-dependently. Moreover, mRNA levels of rPLD1a and rPLD1b showed time-dependent decreases. In contrast, the mRNA level of rPLD2 slightly increased. In sharp contrast to the cells listed above, PLD activity was upregulated during apoptosis, induced by actinomycin D, TNF-α or H202, of Jurkat T cells which mainly express PLDOA. The results obtained suggest that even in resting cells PLD produces survival signals. In response to growth or differentiation signals, it is activated and increases the strength of this signal. On the other hand, apoptotic agents trigger death signal transduction as well as shutting off survival signals including GTPγS-dependent PLD activity. By contrast, unregulated activation of PLD, as observed in Jurkat T cells, also causes cell death. Less

磷脂酶 D (PLD) 可将磷脂，尤其是磷脂酰胆碱 (PC) 水解为磷脂酸 (PA)，而 PA 充当第二信使，并可转化为其他信使分子，例如溶血磷脂酸 (LPA) 和 1,2-二酰基甘油。 (DG) 最近的 cDNA 克隆研究揭示了至少两种同工酶的存在。 (PLD1、PLD2) 在哺乳动物细胞中，除了PLD1a和PLD1b两种选择性剪接形式外，还发现了另一种由油酸等不饱和脂肪酸激活的PLD(PLDOA)。已提出，尽管其分子性质尚不清楚。除了甘油磷脂外，鞘磷脂水解还受到多种应激信号的诱导，包括细胞因子和化疗。鞘磷脂酶水解产生神经酰胺，神经酰胺被视为多种类型细胞（包括 RBL-2H3 细胞、PC12 细胞和 C6 神经胶质瘤细胞）在凋亡过程中的分化和凋亡的第二信使。其中细胞裂解液中 GTPγS 依赖性 PLD 活性随时间下降，rPLD1a 和 rPLD1b 的 mRNA 水平呈时间依赖性下降，相反，rPLD2 的 mRNA 水平略有增加，与上述细胞形成鲜明对比。主要表达 PLDOA 的 Jurkat T 细胞在放线菌素 D、TNF-α 或 H202 诱导的凋亡过程中活性上调。获得的结果表明，即使在静息状态下也是如此。细胞 PLD 会响应生长或分化信号而被激活并增强该信号的强度，另一方面，细胞凋亡剂会触发死亡信号转导并关闭包括 GTPγS 依赖性 PLD 活性在内的生存信号。相比之下，在 Jurkat T 细胞中观察到的 PLD 不受调控的激活也会导致细胞死亡。