MHOR002 expression: Forkhead box O transcription factors both suppress and support breast cancer progression.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE108842 | GEO | 2018/02/11
REPOSITORIES: GEO
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Project description:Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
2011-03-16 | GSE27932 | GEO
Project description:The mammalian FoxO transcription factors - FoxO1, FoxO3, FoxO4 - function in the nucleus to direct transcription of specific gene targets governing cellular survival, proliferation, metabolism, differentiation and oxidative defense. Activation of PI3K by extracellular growth factors leads to AKT-mediated phosphorylation of FoxO1, FoxO3 and FoxO4, resulting in their sequestration in the cytoplasm such that they are unable to regulate their gene targets. Our study identified FoxOs as novel tumor suppressors in kidney cancer (Gan et al, 2010, Cancer Cell). To understand the tumor suppression function of FoxOs in kidney cancer cells, we performed gene expression profiling in human kidney cancer cells upon FoxO1 or FoxO3 reactivation in order to identify the key transcriptomic alterations mediating FoxO tumor suppression function in kidney cancer cells.
2011-10-21 | GSE23926 | GEO
Project description:Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis. Mice were engineered with negative control (MxCre- Fk1 L/L Fk2 L/L Afx L/L) and experimental (MxCre+ Fk1 L/L Fk2 L/L Afx L/L) genotypes. RNAs were isolated from Lung endothelial cells (2 negative controls, 2 experimental), liver sinusoidal endothelial cells (3 negative controls, 3 experimental) and thymus cells (2 negative controls, 2 experimental), and profiled on Affymetrix Mouse Genome 430 2.0 Array.
2011-03-16 | E-GEOD-27932 | biostudies-arrayexpress
Project description:Forkhead Box O (FoxO) transcription factors are conserved proteins involved in the regulation of life span and age-related diseases, such as diabetes and cancer. Stress stimuli or growth factor deprivation promote nuclear localization and activation of FoxO proteins, which - depending on the cellular context - leads to cell cycle arrest or apoptosis. Moreover, FoxOs can control oxidative stress resistance and cell metabolism. In endothelial cells (ECs), they additionally regulate angiogenesis and may promote inflammation and vessel destabilization implicating a role of FoxOs in vascular diseases. In several cancers, FoxO transcription factors exert a tumor-suppressive function, due to their critical role in regulating proliferation and survival. Others and we have previously shown that FoxOs can regulate these processes via two different mechanisms: either by direct binding to FoxO-responsive elements (FRE) at the promoter of target genes or by a poorly understood alternative process that does not require direct DNA binding and regulates key targets in primary human ECs. Here we performed an interaction study in ECs to identify new nuclear FoxO3 interaction partners, which might contribute to FoxO-dependent gene regulation. Mass spectrometry analysis of FoxO3-interacting proteins revealed Transformation/Transcription Domain-Associated Protein (TRRAP), a member of multiple histone acetyltransferase (HAT) complexes, as novel binding partner of FoxO family proteins. TRRAP is required to support FoxO3 transactivation and FoxO3-dependent apoptosis in ECs via transcriptional activation of the proapoptotic Bcl-2 family member BIM. Moreover, FoxO-TRRAP interaction might explain FoxO-induced alternative gene regulation via TRRAP-dependent recruitment to target promoters lacking FRE sequences.
2022-01-20 | PXD027615 | Pride
Project description:The mammalian FoxO transcription factors - FoxO1, FoxO3, FoxO4 - function in the nucleus to direct transcription of specific gene targets governing cellular survival, proliferation, metabolism, differentiation and oxidative defense. Activation of PI3K by extracellular growth factors leads to AKT-mediated phosphorylation of FoxO1, FoxO3 and FoxO4, resulting in their sequestration in the cytoplasm such that they are unable to regulate their gene targets. Our study identified FoxOs as novel tumor suppressors in kidney cancer (Gan et al, 2010, Cancer Cell). To understand the tumor suppression function of FoxOs in kidney cancer cells, we performed gene expression profiling in human kidney cancer cells upon FoxO1 or FoxO3 reactivation in order to identify the key transcriptomic alterations mediating FoxO tumor suppression function in kidney cancer cells. We generated RCC4 and UMRC2 cell lines (two human kidney cancer cells with low endogenous FoxO1 and FoxO3 expression) with stable expression of FoxO1(TA)ERT2 or FoxO3(TA)ERT2 construct, which expressed a fusion protein consisting of FoxO(TA) (containing three Ser/Thr AKT phosphorylation sites mutated to alanine) fused to the T2-modified estrogen receptor (ERT2) moiety. We documented that the FoxO(TA)ERT2 fusion protein sequestered FoxO(TA) in the cytoplasm and that 4OHT treatment resulted in rapid translocation of FoxO(TA)ERT2 into the nucleus. We also established stable cell lines with ERT2 expression as control cell lines. (For simplicity, ERT2, FoxO1(TA)ERT2 and FoxO3(TA)ERT2 cell lines will be referred to as EV (empty vector), FoxO1 and FoxO3, respectively, hereafter). We then conducted comparative transcriptome analysis (using the Human Genome U133 Plus 2.0 Array) of EV, FoxO1, or FoxO3-expressing RCC4 and UMRC2 cells at 12 hours with or without 100 nm 4OHT treatment (cultured in DMEM+10% FBS with puromycin selection). To enrich for more proximal actions of FoxO, we selected the 12 hour time point as time course studies revealed dramatic transcriptional changes of known FoxO targets (such as Cyclin D1), yet no discernable cellular phenotypes (apoptosis and cell cycle arrest). We generated 4 transcriptome datasets: FoxO1 RCC4, FoxO3 RCC4, FoxO1 UMRC2, and FoxO3 UMRC2 (by comparing transcriptome data with or without 4OHT treatment), and normalized these transcriptome data against 4OHT-treated EV cells, which show modest 4OHT-induced transcriptional changes.
2011-10-20 | E-GEOD-23926 | biostudies-arrayexpress
Project description:FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis expression profile between six independant neural stem cell lines (three FoxO null and three wild type) were compared
2009-12-31 | E-GEOD-18308 | biostudies-arrayexpress
Project description:Identification of Foxos target genes in Treg cells. Foxo1and Foxo3 are transcription factors of Foxo family. CD4+Foxp3+ Treg cells isolated from wild-type and Foxo1/3-deficient mice were analyzed by global gene expression profiling. Results indicate Foxos regulate expression of a subset of Treg cell signature genes and genes in control of T cell homeostasis, signaling and metabolism. 2 sets wild-type and Foxo1/3-deficient CD4+Foxp3+ Treg cells
2010-09-13 | E-GEOD-21678 | biostudies-arrayexpress
Project description:Identification of Foxos target genes in Treg cells. Foxo1and Foxo3 are transcription factors of Foxo family. CD4+Foxp3+ Treg cells isolated from wild-type and Foxo1/3-deficient mice were analyzed by global gene expression profiling. Results indicate Foxos regulate expression of a subset of Treg cell signature genes and genes in control of T cell homeostasis, signaling and metabolism.
2010-09-13 | GSE21678 | GEO
Project description:Under stress conditions mammalian cells activate compensatory mechanisms to survive and maintain cellular function. During catabolic conditions, such as low nutrients, systemic inflammation, cancer or infections, protein breakdown is enhanced and aminoacids are released from muscles to sustain liver gluconeogenesis and tissues protein synthesis. Proteolysis in muscle is orchestrated by a set of genes named atrophy-related genes. A system that is activated both in short and prolonged stress conditions is the family of Forkhead Box (Fox) O transcription factors. Here, we report that muscle-specific deletion of FoxO members resulted in protection from muscle loss because FoxO family is required for induction of autophagy-lysosome and ubiquitin-proteasome systems. Importantly, FoxOs are required for Akt activity but not for mTOR signalling underlining the concept that FoxOs are upstream mTOR for the control of protein breakdown when nutrients are lacking. Moreover, FoxO family controls the induction of critical genes belonging to several fundamental stress response pathways such as unfolded protein response, ROS detoxification and translational regulation. Finally, we identify a set of novel FoxO-dependent ubiquitin ligases including the recent discovered MUSA11 and a new one, which we named Specific of Muscle Atrophy and Regulated by Transcription (SMART). Our findings identify the critical role of FoxO in regulating a variety of genes belonging to pathways important for stress-response under catabolic conditions. Gene expression in muscles of muscle-specific FoxO 1,3,4 knock-out mice that were fed normally or starved
2015-04-24 | GSE52667 | GEO
Project description:Sirtuin deacetylases and forkhead box class O (FOXO) transcription factors are central regulators of cell survival, cell cycle and cellular resistance to stress in response to signals from hormones, growth factors and oxidative stress. FOXO activity is modulated by the sirtuins, which function in a NAD+-dependent manner. Sirtuin activity, on the other hand is subject to inhibition by a natural compound nicotinamide (NAM). This study aims to investigate the effects of NAM on the sirtuin pathway and cellular homeostasis. It was hypothesized that NAM inhibits the sirtuin deacetylase activity, which then shifts FOXO-dependent responses away from stress resistance and towards apoptosis. Expression analysis using Affymetrix microarray was employed to determine differential gene expression in HEK293 cells in response to NAM treatment. Data analyses were performed using multiple algorithms, computational methods and interaction analyses. Significant changes in gene expression were detected with the generation of an expansive list of genes and interaction amongst gene groups were identified from the NAM treatment at different concentration. Substantial changes in expression profiles were detected for genes involved in a number of unique cellular pathways and functions, including cell cycle arrest, cellular proliferation and differentiation, metabolism, apoptotic signaling, inflammatory regulation and various disease conditions such as cancer. In addition, this study observed that sirtuin activities exhibit complex cell- and contextdependent behavior in modulating FOXO signaling. Contrasting roles of FOXOs and sirtuins appear to have opposite effects on cellular homeostasis. In addition, the coexistence of reciprocal regulations in this cell system suggested several levels of feedback control and illustrated the complexity of an existing fine-tuned regulatory network system between these two proteins. Future work aims to characterize putative regulators and effectors of sirtuin- and FOXO-related pathways using molecular approaches such and RNA interference knockdown of individual FOXO-isoforms. Inter-connectivity of the pathways will provide invaluable insight into current understanding of cell degeneration diseases such as diabetes, cancers and neurological disorders. Keywords: Serial concentration experiment
2018-12-31 | GSE9707 | GEO