Molecular mechanism of glucocorticoid-induced apoptosis

糖皮质激素诱导细胞凋亡的分子机制

• 批准号: 09670861
• 负责人: MIYASHITA Toshiyuki
• 金额: $ 2.05万
• 依托单位: National Children's Hospital
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670861/
• 关键词: glucocorticoid; apoptosis; caspase; proteolysis; mitochondria; カスパーゼ; プロテアーゼ; Bcl-2

Glucocorticoid (GC) is used for the treatment of leukemias or lymphomas because GC induces apoptosis in certain types of lymphocytes. However, the mechanism of how GC mediates apoptosis is unknown. The purpose of this research project was to elucidate the molecular mechanism of GC-mediated apoptosis. During the period of two years we got the results as follows using 697, a pre-B leukemia cell line.1. Reduction of mitochondrial membrane potential and reactive oxygen production were observed during GC-mediated apoptosis. Both of which, as well as cell death itself were inhibited by a pan-caspase inhibitor, zVAD-fmk.2. On the other hand, a caspase-3-like protease inhibitor, AC-DEVD-CHO inhibited neither of them, while significantly inhibited DNA fragmentation.3.These results indicate the presence of caspase(s), which is inhibited by zVAD-fmk but not by AC-DEVD-CHO, upstream of mitochondrial changes.4.Unexpectedly, caspase-3, a main effector caspase, was not proteolytically activated during GC-induced apoptosis.5. Instead, caspase-6 and -7, other effector caspases, were processed and activated.6. These results indicate that apoptosis triggered by GC has a distinct pathway where caspase-3 is not involved.

糖皮质激素（GC）用于治疗白血病或淋巴瘤，因为GC诱导某些类型的淋巴细胞凋亡。然而，GC如何介导细胞凋亡的机制是未知的。本研究旨在阐明GC介导的细胞凋亡的分子机制。在两年的时间里，我们用前B细胞白血病细胞系697获得了如下结果.在GC介导的凋亡过程中观察到线粒体膜电位和活性氧产生的减少。这两者以及细胞死亡本身都被泛半胱天冬酶抑制剂zVAD-favor抑制。caspase-3样蛋白酶抑制剂AC-DEVD-CHO对上述两种蛋白酶均无抑制作用，但对DNA断裂有显著抑制作用.相反，caspase-6和-7，其他效应caspase，被加工和激活。这些结果表明，由GC触发的凋亡具有独特的途径，其中不涉及caspase-3。

项目成果

Harada,K.: "Bc1-2 protein inhibits oxysterol-induced apoptosis through suppressing CPP32-mediated pathway"FEBS Lett. 411(1). 63-66 (1997)

Harada,K.：“Bc1-2 蛋白通过抑制 CPP32 介导的途径来抑制氧甾醇诱导的细胞凋亡”FEBS Lett。

Nishita,M.,et al.: "Nuclear translocation and increased expression of Bax and disturbance in cell cycle progression without prominent apoptosis induced by hyperthermia." Experimental Cell Research. 244(1). 357-366 (1998)

Nishita, M., et al.：“核易位、Bax 表达增加以及细胞周期进程的紊乱，但热疗不会诱导明显的细胞凋亡。”

Takayama,S.,et al.: "Expression and location of Hsp 70/Hsc-binding anti-apoptotic protein BAG-1 and its variants in normal tissues and tumor cell lines." Cancer Research. 58(14). 3116-3131 (1998)

Takayama,S.,et al.：“Hsp 70/Hsc 结合抗凋亡蛋白 BAG-1 及其变体在正常组织和肿瘤细胞系中的表达和定位。”

Harada K, et al.: "Bcl-2 protein inhibits oxysterol-induced apoptosis through suppressing CPP32-mediated pathway"FEBS Lett. 411(1). 63-66 (1997)

Harada K 等人：“Bcl-2 蛋白通过抑制 CPP32 介导的途径来抑制氧甾醇诱导的细胞凋亡”FEBS Lett。

Nishita,M.: "Nuclear translocation and increased expression of Bax and disturbance in cell cycle progression without prominent apoptosis induced by hyperthermia"Exp Cell Res. 244(1). 357-366 (1998)

Nishita,M.：“核易位和 Bax 表达增加以及细胞周期进程的干扰，但热疗不会诱导明显的细胞凋亡”Exp Cell Res。