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Functional analysis of calcineurin using fission yeast as a model system

使用裂殖酵母作为模型系统进行钙调神经磷酸酶的功能分析

基本信息

批准号：
12670087
负责人：
SHUNTOH Hisato
金额：
$ 1.79万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Calcineurin, a Ca^<2+>- and calmodulin-dependent protein phosphatase (protein phosphatase 2B), is a molecular target for the specific immunosuppressive drugs, such as cyclosporin A or FK506, used in organ transplantation. Calcineurin is enriched in the neural tissues, and also distributes broadly in other tissues. The structure of the protein is highly conserved from yeast to man.We are studying calcineurin signal transduction pathway in the fission yeast Schizosaccharomyces pombe (S. pombe) because this system is amenable to genetics and has many advantages in terms of relevance to higher systems. To identify gene products sharing an essential function with calcineurin, we have screened for mutations that confer synthetic lethality with calcineurin deletion, and have identified ten complementation groups (its1〜10 for immunosuppressant and temperature-sensitive).The combined use of powerful genetics and of specific calcineurin inhibitors in fission yeast identified new components of the calcineurin pathway, and defined new roles of calcineurin in the regulation of the many cellular processes. Recent our data have revealed functional interactions between calcineurin and PI signaling through Its5/PI4P 5 kinase. Calcineurin also paricipates in membrane traffic and septation initiation network (SIN) of fission yeast through its functional connection with the small GTPase Rab/Ypt family protein Its5/Ypt3, and Its10/Cdc7 protein kinase, respectively.These findings provide further insight into the functional role of calcineurin-mediated signal transduction cascades.

钙调磷酸酶，一种Ca 2+ -和钙调蛋白依赖性蛋白磷酸酶(蛋白磷酸酶2B)，是器官移植中使用的特定免疫抑制药物例如环孢菌素A或FK506的分子靶点。钙调磷酸酶在神经组织中富集，并且也广泛分布在其他组织中。该蛋白质的结构从酵母到人类都高度保守。我们正在研究裂殖酵母裂殖酵母（S. pombe）中的钙调神经磷酸酶信号转导途径，因为该系统符合遗传学，并且在与高等系统的相关性方面具有许多优势。为了鉴定与钙调神经磷酸酶共享基本功能的基因产物，我们筛选了通过删除钙调磷酸酶而赋予合成致死性的突变，并鉴定了十个互补组（免疫抑制剂和温度敏感的为 1〜10）。在裂殖酵母中结合使用强大的遗传学和特定的钙调磷酸酶抑制剂，鉴定了钙调磷酸酶途径的新成分，并定义了钙调神经磷酸酶参与许多细胞过程的调节。最近我们的数据揭示了钙调神经磷酸酶和 PI 信号通过 Its5/PI4P 5 激酶之间的功能相互作用。钙调神经磷酸酶还通过其与小 GTPase Rab/Ypt 家族蛋白 Its5/Ypt3 和 Its10/Cdc7 蛋白激酶的功能连接，分别参与裂殖酵母的膜运输和分隔起始网络 (SIN)。这些发现进一步深入了解了钙调神经磷酸酶介导的信号转导级联的功能作用。