Pharmacogenomic research on the immunosuppressant sensitivity using model organisms

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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.