Genetics. Published Articles Ahead of Print: April 19, 2006, Copyright © 2006
doi:10.1534/genetics.106.056895


A more recent version of this article appeared on June 1, 2006.

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A defect in protein farnesylation suppresses a loss of Schizosaccharomyces pombe tsc2+, a homolog of the human gene predisposing tuberous sclerosis complex (TSC)

Yukiko Nakase 1, Keiko Fukuda 1, Yuji Chikashige 2, Chihiro Tsutsumi 2, Daisuke Morita 3, Shinpei Kawamoto 3, Mari Ohnuki 3, Yasushi Hiraoka 2 and Tomohiro Matsumoto 1*

1 Radiation Biology Center, Kyoto University
2 National Institute of Information and Communications Technology
3 Department of Agriculture, Kyoto University

* To whom correspondence should be addressed. E-mail: tmatsumo{at}house.rbc.kyoto-u.ac.jp.

Submitted on February 8, 2006
Revised on March 8, 2006
Accepted on 31 March 2006


Abstract

Mutations in the human Tsc1 and Tsc2 genes predispose to Tuberous Sclerosis Complex (TSC), a disorder characterized by the widespread of benign tumors. Tsc1 and Tsc2 proteins form a complex and serve as a GAP (GTPase activating protein) for Rheb, a GTPase regulating a downstream kinase, mTor. The genome of Schizosaccharomyces pombe contains tsc1+ and tsc2+, homologs of human Tsc1and Tsc2, respectively. In this study we analyzed gene expression profile in a genome-wide 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 {beta}-subunit of a farnesyl transferase 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. Based on these results, we discuss TSC-pathology and possible improvement in chemotherapy for TSC.

Key Words: Farnesyl Transferase, Rhb1 GTPase, Tsc1/2, Tuberous Sclerosis Complex (TSC)




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