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Role of calcineurin in neurons and immune cells

钙调神经磷酸酶在神经元和免疫细胞中的作用

基本信息

批准号：
10480204
负责人：
SHINBASAKI Futoshi
金额：
$ 7.55万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-10480204/
关键词：
phosphorylation calcineurin apoptosis Bcl-2 ischemia cancer neuron immunosuppressants NF-AT 細胞死 Transgenic glia

项目摘要

Calcineurin, a serine/threonine phosphatase 2B, plays an important role in T cell signaling through a transcription factor NF-AT (nuclear factor of activated T cell). We reported previously that calcineurin directly dephosphorylated a pro-apoptotic protein Bad, one of Bcl-2 family member, as well as Bcl-2. Two critical phosphorylation sites S24 and S70 of Bcl-2 were reported to be induced in a certain cancer. For the further analysis of these phosphorylation sites, we prepared the specific antibody against S24P or S70P by synthetic peptides. The antibody against the phosphorylated S70 can detect phosphorylated Bcl-2 at 10 - 50% tumor cells in 10 different tissues of human breast cancer. This antibody also detected the Bcl-2 kinase activity which was induced by anti-cancer agent, Taxol or steroid, dexamethazone, and completely inhibited by both actinomycin D and cycloheximide. This results suggest that Bcl-2 kinase might be de novo synthesised after stimulation.We recently found that th … More e novel function of calcineurin involved in neuronal cell death pathway in rat forebrain ischemic models, in which ischemic reperfusion leads to brain damages in CA1 sector of the hippocampus and the forebrain}. Dephosphorylation of Bad and the release of cytochrome c from mitochondria were detected in CA1, but not in CA3 or in DG after 24 hours of ischemia. The calcineurin activity increased 4 folds in these regions 1 hour after ischemia, and then gradually reached a maximal level (6 folds) at 24 hours later. Pre-treatment with CsA or FK506 suppressed the calcineurin activity in each region. The area of high T2WI (T2-weighted image) in diffusion MRI appeared in the putamen and the hippocampal region 6-12 hours after ischemia. Seven days after ischemia, the areas of high T2WI appeared strongly in forebrain and CA1, which were consisted of massive dead cells and slight edema in pathological staining and EM. Surprisingly, CsA totally (over 95%) suppressed the delayed neuronal cell death and edema while Fk506 effected only 40 - 50% of them.Cyclophilin D expressed in mitochondria was reported to regulate cytochrome c release by protecting MPT (mito-chondrial permeability transition) pores. Our results suggest that CsA has the strong neuroprotective effect through suppression of both calcineurin and cyclophilin D. Moreover, CsA can be applied to treat ischemic brain damages caused by cerebral infarction, embolism and hemorrhages. Less

钙调神经磷酸酶是一种丝氨酸/苏氨酸磷酸酶2B，通过转录因子NF-AT（活化T细胞核因子）在T细胞信号转导中起重要作用。我们以前报道过，钙调磷酸酶直接去磷酸化促凋亡蛋白Bad，Bcl-2家族成员之一，以及Bcl-2。据报道，Bcl-2的两个关键磷酸化位点S24和S70在某种癌症中被诱导。为了进一步分析这些磷酸化位点，我们用合成肽制备了抗S24 P或S70 P的特异性抗体。针对磷酸化S70的抗体可以在10种不同的人乳腺癌组织中检测10 - 50%肿瘤细胞中的磷酸化Bcl-2。该抗体还检测到Bcl-2激酶活性，该活性被抗癌剂紫杉醇或类固醇地塞米松诱导，并被放线菌素D和放线菌酮完全抑制。这一结果表明，Bcl-2激酶可能是在刺激后重新合成的。 ...更多信息钙调神经磷酸酶在大鼠前脑缺血模型中参与神经元细胞死亡途径的新功能，其中缺血再灌注导致海马和前脑的CA 1区的脑损伤。缺血24小时后，在CA 1中检测到Bad的去磷酸化和线粒体细胞色素c的释放，但在CA 3或DG中未检测到。缺血后1h，这些区域的钙调神经磷酸酶活性增加4倍，24h后逐渐达到最高水平（6倍）。CsA或FK506预处理抑制各区域的钙调神经磷酸酶活性。脑缺血后6-12 h弥散MRI T2加权像高T2区出现于壳核和海马区。缺血7d后，前脑和CA1区T2WI高信号区明显，病理染色和电镜下可见大量死亡细胞和轻度水肿。CsA可完全抑制迟发性神经细胞死亡和水肿（95%以上），而Fk 506仅能抑制40 - 50%的迟发性神经细胞死亡和水肿。结果提示，CsA通过抑制钙调神经磷酸酶和亲环素D的表达而具有较强的神经保护作用。CsA还可用于治疗脑梗死、脑栓塞、脑血管病等引起的缺血性脑损伤。少