Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling.
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in one of two tumor suppressor genes, TSC1 and TSC2. Here, we show that absence of Drosophila Tsc1/2 leads to constitutive dS6K activation and inhibition of dPKB, the latter effect being relieved by loss of dS6K. In contrast, the dPTEN tumor suppressor, a negative effector of PI3K, has little effect on dS6K, but negatively regulates dPKB. More importantly, we demonstrate that reducing dS6K signaling rescues early larval lethality associated with loss of dTsc1/2 function, arguing that the S6K pathway is a promising target for the treatment of TSC.
Radimerski
Thomas
T
Friedrich Miescher Institute for Biomedical Research, CH-4058, Basel, Switzerland.
Montagne
Jacques
J
Hemmings-Mieszczak
Maja
M
Thomas
George
G
D000818:Animals; D002455:Cell Division / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005123:Eye / Q000254:growth & development; D017344:Genes, Insect; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor; D009154:Mutation; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012330:RNA, Double-Stranded / Q000235:genetics / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014921:Wings, Animal / Q000254:growth & development
D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012330:RNA, Double-Stranded; D019893:Ribosomal Protein S6 Kinases; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate