CROSS-TALK OF MEMBRANE LIPID SIGNALING IN CELL DEATH AND SURVIVAL

细胞死亡和存活中膜脂信号传导的交叉对话

• 批准号: 14370064
• 负责人: NOZAWA Yoshinori
• 金额: $ 8.13万
• 依托单位: GIFU INTERNATIONAL INSTITUTE OF BIOTECHNOLOGY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370064/
• 关键词: APOPTOSIS; SURVAIVAL; Pyk2; PHOSPHOLIPASE D; AKT; PHOSPHATIDYLINOSITOL 3-KINASE; ERK; スフィンゴシンキナーゼ; ホスホリパーゼD

We have previously proposed the notion that phospholipase D (PLD) plays an important role in the anti-apototic or survival signaling pathway. When PC12 cells were exposed to the oxidative stress (H_2O_2), the PLD activity was found to greatly increase at the early stage. It was demonstrated that the Pyk2 which acts as a scarffold and Src kinase are colsely associated with the H_2O_2-induced PLD activation. In addition, Pyk2 was found to be physically interacted with PLD as inferred by co-immunoprecipitation. Thus it was concluded that the Pyk2/Src/Akt pathway is of primary importance for the survival signaling at the early phase after the H_2O_2 stress.On the other hand, it has been known that sphingosine kinase produces sphingosine-1-phosphate whth exerts a survival signaling by its specific receptor activation (S1Ps). Furthermore, it was shown that the sphingosine kinase was much higher in the activity and protein expression level in camptothecin (CPT)-resistant PC3 cells as compared to CPT-sensitive LNCaP cells of human prostate cancer cells. Also, we have obtained the unexpected, interesting finding that CPT treatment enhanced the SPHK activity in a time-dependent manner, but the underlying mechanism remains to be defined. This can explain at least in part the CPT-resistance of PC3 cells.

我们之前提出了磷脂酶D （PLD）在抗凋亡或生存信号通路中起重要作用的概念。当PC12细胞暴露于氧化应激（H_2O_2）时，PLD活性在早期显著升高。结果表明，作为支架的Pyk2和Src激酶与h_2o_2诱导的PLD活化密切相关。此外，通过共免疫沉淀推断，Pyk2与PLD存在物理相互作用。由此可见，Pyk2/Src/Akt通路在H_2O_2胁迫后早期存活信号通路中起重要作用。另一方面，鞘氨醇激酶产生鞘氨醇-1-磷酸，并通过其特异性受体激活（S1Ps）发挥生存信号。此外，我们还发现在喜树碱（CPT）耐药的PC3细胞中，鞘氨醇激酶的活性和蛋白表达水平远高于对CPT敏感的LNCaP细胞。此外，我们还获得了意想不到的有趣发现，即CPT治疗以一种时间依赖的方式增强了SPHK的活性，但其潜在机制仍有待确定。这至少可以部分解释PC3细胞对cpt的抵抗。

项目成果

Wang, S.: "Two forms of membrane-bound sphingosine kinase in tetrahymena and activity changes during growth and the cell cycle"J.Eukaryot.Microbiol.. 49(4). 305-311 (2002)

Wang, S.：“四膜虫中膜结合鞘氨醇激酶的两种形式以及生长和细胞周期过程中的活性变化”J.Eukaryot.Microbiol.. 49(4)。

Banno, Y.: "Involvement of phospholipase D in insulin-like growth factor-I-induced activation of intracellular signal-regulated kinase, but not phosphatydylinositol 3-kinase or Akt, in Chinese hamster ovary cells"Biochem.J.. 369. 363-368 (2003)

Banno，Y.：“在中国仓鼠卵巢细胞中，磷脂酶 D 参与胰岛素样生长因子 I 诱导的细胞内信号调节激酶激活，但不参与磷脂酰肌醇 3-激酶或 Akt”Biochem.J. 369。

Chen, J.et al.: "The inhibitory effect of local anesthetics on bradykinin-induced phospholipase D activation in rat pheochromocytoma PC12 cells."Anesth.Analg.. 95. 88-97 (2002)

Chen, J. 等人：“局麻药对大鼠嗜铬细胞瘤 PC12 细胞中缓激肽诱导的磷脂酶 D 激活的抑制作用。”Anesth.Analg.. 95. 88-97 (2002)

Nozawa, Y.et al.: "Involvement of phospholipase D in insulin-like growth factor induced activation of extracellular signal-regulated kinase, but not phosphatydylinositol 3-kinase or Akt, in Chinese hamster ovary cell."Biochem.J.. 369. 363-368 (2003)

Nozawa, Y.等人：“胰岛素样生长因子中磷脂酶 D 的参与诱导了中国仓鼠卵巢细胞中细胞外信号调节激酶的激活，但不是磷脂酰肌醇 3-激酶或 Akt。”Biochem.J. 369

Yamada, M.et al.: "Overexpression of PLD prevents actinomycin D-induced apoptosis through potentiation of PI3K signaling pathways in Chinese hamster ovary cells."Biochem.J.. 378. 1-8 (2004)

Yamada, M.等人：“PLD 的过度表达通过增强中国仓鼠卵巢细胞中的 PI3K 信号通路来防止放线菌素 D 诱导的细胞凋亡。”Biochem.J.. 378. 1-8 (2004)