naa a22 4500 528784897 20180924065517.0 cr unu---uuuuu 180924e20101231xx s 000 0 eng 10.3929/ethz-b-000029992 doi 10.1371/journal.pone.0015171 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/29992 The Drosophila FoxA Ortholog Fork Head Regulates Growth and Gene Expression Downstream of Target of Rapamycin [Elektronische Daten] [Margret H. Bülow, Ruedi Aebersold, Michael J. Pankratz, Martin A. Jünger] PLoS ONE Open access ethresearch Forkhead transcription factors of the FoxO subfamily regulate gene expression programs downstream of the insulin signaling network. It is less clear which proteins mediate transcriptional control exerted by Target of rapamycin (TOR) signaling, but recent studies in nematodes suggest a role for FoxA transcription factors downstream of TOR. In this study we present evidence that outlines a similar connection in Drosophila, in which the FoxA protein Fork head (FKH) regulates cellular and organismal size downstream of TOR. We find that ectopic expression and targeted knockdown of FKH in larval tissues elicits different size phenotypes depending on nutrient state and TOR signaling levels. FKH overexpression has a negative effect on growth under fed conditions, and this phenotype is not further exacerbated by inhibition of TOR via rapamycin feeding. Under conditions of starvation or low TOR signaling levels, knockdown of FKH attenuates the size reduction associated with these conditions. Subcellular localization of endogenous FKH protein is shifted from predominantly cytoplasmic on a high-protein diet to a pronounced nuclear accumulation in animals with reduced levels of TOR or fed with rapamycin. Two putative FKH target genes, CG6770 and cabut, are transcriptionally induced by rapamycin or FKH expression, and silenced by FKH knockdown. Induction of both target genes in heterozygous TOR mutant animals is suppressed by mutations in fkh. Furthermore, TOR signaling levels and FKH impact on transcription of the dFOXO target gene d4E-BP, implying a point of crosstalk with the insulin pathway. In summary, our observations show that an alteration of FKH levels has an effect on cellular and organismal size, and that FKH function is required for the growth inhibition and target gene induction caused by low TOR signaling levels. Creative Commons Attribution 3.0 Unported http://creativecommons.org/licenses/by/3.0 ethresearch Bülow Margret H. joint author Aebersold Ruedi joint author Pankratz Michael J. joint author Jünger Martin A. joint author PLoS ONE Lawrence, KS, USA : Public Library of Science 5 (12), p. e15171 1932-6203 http://hdl.handle.net/20.500.11850/29992 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/29992 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Bülow Margret H. joint author ETHRESEARCH 700 1- Aebersold Ruedi joint author ETHRESEARCH 700 1- Pankratz Michael J. joint author ETHRESEARCH 700 1- Jünger Martin A. joint author ETHRESEARCH 773 0- PLoS ONE Lawrence, KS, USA : Public Library of Science 5 (12), p. e15171 1932-6203 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access