FOXO-regulated transcription restricts overgrowth of Tsc mutant organs.
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.
Harvey
Kieran F
KF
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. kieran.harvey@petermac.org
Mattila
Jaakko
J
Sofer
Avi
A
Bennett
F Christian
FC
Ramsey
Matthew R
MR
Ellisen
Leif W
LW
Puig
Oscar
O
Hariharan
Iswar K
IK
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
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