A defect in protein farnesylation suppresses a loss of Schizosaccharomyces pombe tsc2+, a homolog of the human gene predisposing to tuberous sclerosis complex.
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 beta-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.
Nakase
Yukiko
Y
Radiation Biology Center, Kyoto University, Japan.
Fukuda
Keiko
K
Chikashige
Yuji
Y
Tsutsumi
Chihiro
C
Morita
Daisuke
D
Kawamoto
Shinpei
S
Ohnuki
Mari
M
Hiraoka
Yasushi
Y
Matsumoto
Tomohiro
T
D001483:Base Sequence; D003001:Cloning, Molecular; D004271:DNA, Fungal / Q000235:genetics; D051231:Farnesyltranstransferase / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D006801:Humans; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017368:Protein Prenylation; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013045:Species Specificity; D013489:Suppression, Genetic; D014402:Tuberous Sclerosis / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D004271:DNA, Fungal; D029702:Schizosaccharomyces pombe Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C471572:Tsc1 protein, S pombe; C471573:Tsc2 protein, S pombe; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051231:Farnesyltranstransferase; D020558:GTP Phosphohydrolases; C412832:Rhb1 protein, S pombe; D009584:Nitrogen