Involvement of calcineurin in apoptosis induced by microtubule dysfunction

钙调神经磷酸酶参与微管功能障碍诱导的细胞凋亡

• 批准号: 14580746
• 负责人: YAMAMOTO Hideyuki
• 金额: $ 1.86万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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-14580746/
• 关键词: Apoptosis; Bcl-2; Calcineurin; Cancer-cells; Cyclosporin A; Dephosphorylation; FK506; Neurons; 脱燐酸化反応; タキソール

Taxol binds to microtubules and induces apoptosis of various cancer cells. Several lines of evidence indicate that taxol induces apoptosis through activation of c-Jun N-terminal kinase (JNK) and the concomitant phosphorylation of B-cell leukemia/lymphoma-2 (Bcl-2) by the activated JNK. Calcineurin is a serine/threonine protein phosphatase and has been reported to be involved in dephosphorylation of Bcl-2. We found that T24 cells derived from human urinary bladder cancer were resistant to taxol. A combination treatment with taxol and cyclosporin A (CsA) or FK506, calcineurin inhibitors, resulted in loss of calcineurin activity and enhancement of phosphorylation of Bcl-2. In addition, treatment of the cells with CsA or FK506 significantly decreased the expression of Bcl-2 at both the protein and mRNA levels. Interestingly, apoptosis of T24 cells was induced by low of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic concentration of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic actions via the dephosphorylation of Bcl-2 and the induction of the gene expression of Bcl-2. In neurons, tau protein binds to microtubules and regulates the microtubule functions in axons. We found that Ca^<2+>, calmodulin-dependent protein kinase II (CaM kinase II) phosphorylated tau at tubulin binding sites and inhibited the binding of tau to microtubules. These results may suggest that CaM kinase II is involved in apoptosis via the phosphorylation of tau.

紫杉醇与微管结合并诱导各种癌细胞的凋亡。几条证据表明，紫杉醇通过激活C-JUN N末端激酶（JNK）的激活以及B细胞白血病/淋巴瘤-2（BCL-2）的磷酸化诱导凋亡。钙调蛋白是一种丝氨酸/苏氨酸蛋白磷酸酶，据报道与Bcl-2的去磷酸化有关。我们发现源自人尿膀胱癌的T24细胞对紫杉醇具有抗性。用紫杉醇和环孢菌素A（CSA）或FK506，钙调神经蛋白抑制剂的组合处理导致钙调蛋白活性的损失和BCL-2磷酸化的增强。此外，用CSA或FK506对细胞进行处理可显着降低Bcl-2在蛋白质和mRNA水平上的表达。有趣的是，在CSA或FK506存在下，紫杉醇的低紫杉醇诱导了T24细胞的凋亡。这些结果表明，在CSA或FK506存在下，钙调神经蛋白具有抗凋亡浓度的紫杉醇。这些结果表明，钙调蛋白通过Bcl-2的去磷酸化和Bcl-2基因表达的诱导具有抗凋亡作用。在神经元中，tau蛋白与微管结合并调节轴突中的微管功能。我们发现Ca^<2+>，钙调蛋白依赖性蛋白激酶II（CAM激酶II）在微管蛋白结合位点磷酸化tau，并抑制了TAU与微管的结合。这些结果可能表明CAM激酶II通过TAU的磷酸化参与凋亡。

项目成果

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Yamamoto, H.: "Involvement of Ca^<2+>/calmodulin-dependent phosphorylation of synapsin I in insulin exocytosis."J.Pharmacol.Sci.. 93. 30-34 (2003)

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Yonehara, T.：“用黄体生成素 β 亚基互补脱氧核糖核酸稳定转染的 αT3-1 细胞的表征。Endocrine J.. 50. 341-354 (2003)

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