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J. Biol. Chem., Vol. 278, Issue 29, 26976-26982, July 18, 2003

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Ubiquitin Pathway Proteins Influence the Mechanism of Action of the Novel Immunosuppressive Drug FTY720 in Saccharomyces cerevisiae^*

Carole A. Welsch , Shinji Hagiwara , Jean Francois Goetschy  and N. Rao Movva  ¶

From the Transplantation Research, Novartis Pharma AG, CH-4002 Basel, Switzerland and the Tsukuba Research Laboratories, GlaxoSmith Kline KK, 300-4247 Tsukubashi, Ibaraki, Japan

FTY720 is an immunosuppressive drug in clinical development for transplant graft protection in humans. This agent is of particular interest because, unlike currently available regimes, it acts to sequester lymphocytes without causing cytotoxicity or blocking differentiation and growth potential. In an effort to elucidate the mechanism of action of FTY720, and identify its downstream effectors, we have screened genomic libraries and spontaneous mutants of the model system Saccharomyces cerevisiae for resistance to FTY720. We identified several proteins and pathways as being involved in the mechanism of action of FTY720. We show specifically that the two amino acid transporters TAT1 and TAT2, the two ubiquitin proteases UBP5 and UBP11, and the heat shock protein CAJ1 confer growth resistance to FTY720 when overexpressed. Another amino acid transporter, GNP1, and the ubiquitin structural gene UBI4 as well as the ubiquitin ligase RSP5, and its binding protein BUL1 confer growth resistance in a mutated form. Supporting the importance of amino acid transport in the growth resistance phenotype of S. cerevisiae to the immunosuppressive agent FTY720, a prototrophic strain was more resistant to FTY720 than the isogenic auxotroph. To further explore these results, the effects on amino acid uptake and protein degradation were measured in the presence of FTY720. Due to the high conservation of these proteins and pathways between yeast and humans, these results may provide valuable insights into the mechanism of action of FTY720 in lymphocyte sequestration in humans.

Received for publication, December 23, 2002 , and in revised form, April 4, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Transplantation Research, Novartis Pharma A.G., WSJ 386-906, CH-4002 Basel, Switzerland. Tel.: 41-61-3247995; Fax: 41-61-3247429; E-mail: rao.movva{at}pharma.novartis.com.

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