title: FOXO-regulated transcription restricts overgrowth of Tsc mutant organs.
abstract: FOXO is thought to function as a repressor of growth that is, in turn, inhibited by insulin signaling. However, inactivating mutations in Drosophila melanogaster FOXO result in viable flies of normal size, which raises a question over the involvement of FOXO in growth regulation. Previously, a growth-suppressive role for FOXO under conditions of increased target of rapamycin (TOR) pathway activity was described. Here, we further characterize this phenomenon. We show that tuberous sclerosis complex 1 mutations cause increased FOXO levels, resulting in elevated expression of FOXO-regulated genes, some of which are known to antagonize growth-promoting pathways. Analogous transcriptional changes are observed in mammalian cells, which implies that FOXO attenuates TOR-driven growth in diverse species.
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. kieran.harvey@petermac.org
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Harvey
authors.forename: Jaakko
authors.initials: J
authors.lastname: Mattila
authors.forename: Avi
authors.initials: A
authors.lastname: Sofer
authors.forename: F Christian
authors.initials: FC
authors.lastname: Bennett
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ramsey
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.forename: Iswar K
authors.initials: IK
authors.lastname: Hariharan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000013:Congenital Abnormalities / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology* / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011494:Protein Kinases; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D013045:Species Specificity; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; C477334:FOXO protein, Drosophila; C515347:TSC1 protein, Drosophila; C416303:target of rapamycin protein, Drosophila