Pharmacogenomic research on the immunosuppressant sensitivity using model organisms

钙调神经磷酸酶是一种钙和钙调蛋白依赖的蛋白磷酸酶(蛋白磷酸酶2B)，是用于器官移植的特异性免疫抑制药物如环孢素A或FK506的分子靶点。钙调神经磷酸酶在神经组织中含量丰富，在其他组织中也有广泛分布。蛋白质的结构从酵母到人都是高度保守的。我们正在研究裂殖酵母裂殖酵母(S.pombe)对免疫抑制药物的敏感性，因为这个系统符合遗传学，并且在与更高系统的相关性方面具有许多优势。我们已经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(免疫抑制和温度敏感的ITS 1~10)。结合强大的遗传学和分裂酵母中特定的钙调神经磷酸酶抑制剂的使用，鉴定了钙调神经磷酸酶途径的新成分，并确定了钙调神经磷酸酶在许多细胞过程中的调节作用。最近，我们的数据揭示了钙调神经磷酸酶通过其5/PI4P5激酶与IP信号之间的功能相互作用。钙调神经磷酸酶还分别通过与小的GTP酶Rab/YPT家族蛋白Its5/Ypt3和Its10/CDC7蛋白激酶的功能连接，参与分裂酵母的膜运输和分离启动网络(SIN)。考虑到人和分裂酵母之间信号转导通路的保守，这些发现为进一步了解免疫抑制治疗对器官移植不利的分子机制提供了依据。

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.