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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）水解磷脂，特别是磷脂酰胆碱（PC）生成磷脂酸（PA）和胆碱。PA作为第二信使分子，可以转化为其他信使分子，如溶血磷脂酸（LPA）和1,2-二酰基甘油（DG）。最近的cDNA克隆研究表明，哺乳动物细胞中至少存在两种同工酶（PLD1, PLD2）。对于PLD1，已经确定了PLD1a和PLD1b两种可选择拼接的形式。除此之外，人们还提出了另一种由油酸等不饱和脂肪酸激活的PLD (PLDOA)，尽管其分子性质尚不清楚。除了甘油磷脂外，鞘磷脂水解还可由多种应激信号诱导，包括细胞因子和化疗药物。鞘磷脂酶水解鞘磷脂产生神经酰胺，神经酰胺被认为是分化和凋亡的第二信使。n -乙酰鞘氨醇是一种膜渗透性类似物，可抑制几种类型细胞的PLD活性，包括RBL-2H3细胞、PC12细胞和C6胶质瘤细胞。在细胞凋亡过程中，细胞裂解物中gtp - γ - s依赖性PLD活性呈时间依赖性下降。此外，rPLD1a和rPLD1b的mRNA水平呈时间依赖性下降。相比之下，rPLD2 mRNA水平略有升高。与上述细胞形成鲜明对比的是，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，PLD活性上调。结果表明，即使在静止细胞中，PLD也会产生存活信号。在响应生长或分化信号时，它被激活并增加该信号的强度。另一方面，凋亡因子触发死亡信号转导，并关闭生存信号，包括gtp γ s依赖性PLD活性。相比之下，在Jurkat T细胞中观察到的PLD不受调节的激活也会导致细胞死亡。少