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A defect in protein farnesylation suppresses a loss of fission yeast tsc2

ABSTRACT: 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 (GTP activating protein) for Rheb, a GTPase regulating a downstream kinase, mTor. The fission yeast genome 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 a gene normally repressed by glucose (inv1+) are more induced. We also demonstrate that a mutation (cpp1-1) in a gene encoding aβ-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 the TSC-pathology and possible improvement in chemotherapy for TSC. Keywords: Keywards: Nitrogen starvation, Dtsc1. Dtsc2

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE4449 | GEO | 2006/06/13

SECONDARY ACCESSION(S): PRJNA94721

REPOSITORIES: GEO

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2010-07-30 | E-GEOD-21755 | biostudies-arrayexpress

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Distinctive responses to nitrogen starvation in the dominant active mutants of the fission yeast Rheb GTPase.

Project description:Rheb, a ras-like small GTPase conserved from human to yeast, controls Tor kinase and plays a central role in regulation of cell growth depending on extracellular conditions. Fission yeast Rheb regulates amino acid uptake as well as response to nitrogen starvation. In this study we generated two mutants of Rheb, rhb1-DA4 and rhb1-DA8, and characterized them genetically. V17A mutation within the G1 box defined for the ras-like GTPases was responsible for rhb1-DA4, and Q52R I76F within the switch II domain for 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. Under nitrogen-rich conditions, Rheb stimulates Tor kinase, which, in turn, suppresses the response to nitrogen starvation. While amino acid uptake was prevented by both rhb1-DA4 and rhb1-DA8 in a dominant fashion, the response to nitrogen starvation was prevented only by rhb1-DA4. rhb1-DA8 thereby allowed genetic dissection of the Rheb-dependent signaling cascade. We postulate that Rheb in fission may have two downstream elements, Tor kinase for regulation of the response to nitrogen starvation and the other element for regulation of amino acid uptake. Gene expression profile under nitrogen starvation in fission yeast. Type of experiment: Comparing between vegetatively-growing control cells and cells 3 hrs after nitrogen starvation. Experimental factor: Gene expression profile after nitrogen starvation in the rhb1-D4 or rhb1-D8 cells. Quality control steps taken: All experiments were repeated more than twice except for the tsc2D which was previously reported. Keywards: Nitrogen starvation, rhb1-D4, rhb1-D8

2009-09-28 | E-GEOD-14626 | biostudies-arrayexpress

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