Pharmacogenomic research on the immunosuppressant sensitivity using model organisms

钙调磷酸酶是一种Ca^<2+>-和钙调素依赖性蛋白磷酸酶（蛋白磷酸酶2B），是器官移植中使用的特异性免疫抑制药物（如环孢素a或FK506）的分子靶点。钙调磷酸酶丰富于神经组织，也广泛分布于其他组织。这种蛋白质的结构从酵母到人类都是高度保守的。我们正在研究分裂酵母pombe Schizosaccharomyces （S. pombe）的免疫抑制药物敏感性，因为这个系统是符合遗传学的，并且在与高等系统相关方面具有许多优势。我们筛选了对免疫抑制剂、FK506和环孢素A敏感的突变，并鉴定了10个互补基团（免疫抑制剂和温度敏感的互补基团为1~10）。结合强大的遗传学和裂变酵母中特定的钙调磷酸酶抑制剂，发现了钙调磷酸酶途径的新成分，并确定了钙调磷酸酶在许多细胞过程调节中的新作用。最近我们的数据揭示了钙调磷酸酶通过Its5/ pi4p5激酶与IP信号传导之间的功能相互作用。钙调磷酸酶还通过与GTPase Rab/Ypt家族小蛋白Its5/Ypt3和Its10/Cdc7蛋白激酶的功能连接，参与裂变酵母的膜运输和分离起始网络（SIN）。考虑到人与分裂酵母菌之间信号转导通路的保守性，这些发现为进一步了解免疫抑制治疗对器官移植不良反应的分子机制提供了新的思路。

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 immunosuppressive drug sensitivity 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. We have screened for mutations that confer sensitivity to immunosuppressant, FK506 and cyclosporin A, 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 IP signaling through Its5/PI4P 5 kinase. Calcineurin also participates in membrane traffic and separation 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.Taking account of the conservation of the signal transduction pathway between human and the fission yeast, these findings provide further insight into the molecular mechanisms of adverse effects of immunosuppressant therapy upon organ transplantation.