Originally published as Genetics Published Articles Ahead of Print on April 19, 2006.

Genetics, Vol. 173, 569-578, June 2006, Copyright © 2006
doi:10.1534/genetics.106.056895

A Defect in Protein Farnesylation Suppresses a Loss of Schizosaccharomyces pombe tsc2⁺, a Homolog of the Human Gene Predisposing to Tuberous Sclerosis Complex

Yukiko Nakase^*,, Keiko Fukuda^*,, Yuji Chikashige, Chihiro Tsutsumi, Daisuke Morita, Shinpei Kawamoto, Mari Ohnuki, Yasushi Hiraoka and Tomohiro Matsumoto^*,,1

^* Radiation Biology Center, Kyoto University, Yoshida-Konoe cho, Sakyo ku, Kyoto, Japan, 606-8501, Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwake cho, Sakyo ku, Kyoto, Japan, 606-8502, Department of Agriculture, Kyoto University, Kitashirakawa-Oiwake cho, Sakyo ku, Kyoto, Japan, 606-8502 and Cell Biology Group, Kansai Advanced Research Center National Institute of Information and Communications Technology, Kobe, Hyogo, Japan, 651-2492

¹ Corresponding author: Radiation Biology Center, Kyoto University, Yoshida-Konoe cho, Sakyo Ku, Kyoto, Japan 606-8501.
E-mail: tmatsumo{at}house.rbc.kyoto-u.ac.jp

Mutations in the human Tsc1 and Tsc2 genes predispose to tuberous sclerosis complex (TSC), a disorder characterized by the wide spread of benign tumors. Tsc1 and Tsc2 proteins form a complex and serve as a GTPase-activating protein (GAP) for Rheb, a GTPase regulating a downstream kinase, mTOR. The genome of Schizosaccharomyces pombe contains tsc1⁺ and tsc2⁺, homologs of human Tsc1 and Tsc2, respectively. In this study we analyzed the gene expression profile on a genomewide scale and found that deletion of either tsc1⁺ or tsc2⁺ affects gene induction upon nitrogen starvation. Three hours after nitrogen depletion genes encoding permeases and genes required for meiosis are less induced. Under the same condition, retrotransposons, G1-cyclin (pas1⁺), and inv1⁺ are more induced. We also demonstrate that a mutation (cpp1-1) in a gene encoding a ß-subunit of a farnesyltransferase can suppress most of the phenotypes associated with deletion of tsc1⁺ or tsc2⁺. When a mutant of rhb1⁺ (homolog of human Rheb), which bypasses the requirement of protein farnesylation, was expressed, the cpp1-1 mutation could no longer suppress, indicating that deficient farnesylation of Rhb1 contributes to the suppression. On the basis of these results, we discuss TSC pathology and possible improvement in chemotherapy for TSC.

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