Using genetic buffering relationships identified in fission yeast to reveal susceptibilities in cells lacking hamartin or tuberin function

摘要

Tuberous sclerosis complex is an autosomal dominant disorder characterized by benign tumors arising from the abnormal activation of mTOR signaling in cells lacking TSC1 (hamartin) or TSC2 (tuberin) activity. To expand the genetic framework surrounding this group of growth regulators, we utilized the model eukaryoteSchizosaccharomyces pombeto uncover and characterize genes that buffer the phenotypic effects of mutations in the orthologoustsc1ortsc2loci. Our study identified two genes:fft3(encoding a DNA helicase) andypa1(encoding a peptidyle-prolyl cis/trans isomerase). While the deletion offft3orypa1has little effect in wild-type fission yeast cells, their loss intsc1Δortsc2Δbackgrounds results in severe growth inhibition. These data suggest that the inhibition of Ypa1p or Fft3p might represent an ‘Achilles’ heel’ of cells defective in hamartin/tuberin function. Furthermore, we demonstrate that the interaction betweentsc1/tsc2andypa1can be rescued through treatment with the mTOR inhibitor, torin-1, and thatypa1Δcells are resistant to the glycolytic inhibitor, 2-deoxyglucose. This identifiesypa1as a novel upstream regulator of mTOR and suggests that the effects ofypa1loss, together with mTOR activation, combine to result in a cellular maladaptation in energy metabolism that is profoundly inhibitory to growth.