Fission Yeast Model Study for Dissection of TSC Pathway
Final rept. 30 Dec 2004-29 Mar 2010
KYOTO UNIV (JAPAN)
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Tuberous sclerosis complex TSC is an autosomal dominant disorder associated with mutations in two different genes, TSC1 and TSC2, which cause benign tumors called hamartomas. In the fission yeast model study, we have demonstrated that a mutation in a gene encoding a -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 a tsc2-null strain. The result would suggest that a drug inhibiting a farnesyl transferase may be used for treatment of TSC. We have also generated two mutants, rhb1-DA4 and rhb1-DA8. In fission yeast, two events, induction of a meiosis initiating gene mei2 and cell division without cell growth, are a typical response to nitrogen starvation. We have found that while amino acid uptake is prevented by both rhb1-DA4 and rhb1- DA8, the response to nitrogen starvation is prevented only by rhb1-DA4. We postulate that the signaling cascade may branch below Rhb1. If human Rheb GTPase works in a similar manner, the efficacy of Rapamycin, an anti-TSC drug targeting mTOR, may be limited.
- Anatomy and Physiology
- Medicine and Medical Research