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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.

SUBMITTER: Harvey KF

PROVIDER: S-EPMC2265581 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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FOXO-regulated transcription restricts overgrowth of Tsc mutant organs.

Harvey Kieran F KF 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

The Journal of cell biology 20080201 4

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 compl ...[more]

PMID: 18299344

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Control of endothelial quiescence by FOXO-regulated metabolites.

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The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth.

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FOXO transcription factors throughout T cell biology.

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FoxO restricts growth and differentiation of cells with elevated TORC1 activity under nutrient restriction.

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A FOXO-dependent replication checkpoint restricts proliferation of damaged cells

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FoxO transcription factors 1 regulate mouse preimplantation embryo development.

Project description:PURPOSE:The aim of the present study is to investigate role of FoxO transcription factors in preimplantation embryo development by knocking down FoxO1, FoxO3, and FoxO4 genes and also to assess cell cycle arrest related proteins, p53 and p21, and apoptosis-related proteins, fas ligand (FASL), and cleaved caspase 3. METHODS:Knockdown of FoxOs using siRNA was confirmed utilizing RT-PCR and qRT-PCR in gene level and using immunofluorescence in protein level. Following knockdown of FoxO1, FoxO3, and FoxO4 in two-cell mouse embryos with or without resveratrol treatment; developmental competence of embryos and expression patterns of SIRT1, p53, p21, FASL, and CLEAVED CASPASE 3 proteins in embryos by immunofluorescence were assessed after 48 h. ROS levels were measured in knockdown embryos. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to determine resveratrol dose. RESULTS:Successful knockdown of FoxO genes in mouse embryos utilizing a non-invasive siRNA method was achieved. Significantly, knockdown of FoxO genes impaired preimplantation embryo development which cannot be prevented by resveratrol treatment. Immunofluorescence results showed that resveratrol could protect embryos from cell cycle arrest and apoptosis. FOXO proteins regulate apoptosis and cell cycle related proteins in mouse preimplantation embryos. Moreover, there might be an autofeedback mechanism where FOXO1, FOXO3, and FOXO4 regulate SIRT1 protein expression. CONCLUSIONS:These results suggest that FOXO transcription factors could contribute to mouse preimplantation embryo development, and it remains to investigate whether they have crucial roles in human preimplantation embryo and infertility.

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FOXO transcription factors in non-alcoholic fatty liver disease.

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