Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells.

Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic.

FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue.

Objective: Forkhead box O (FoxO) transcription factors represent evolutionarily conserved targets of insulin signaling, regulating metabolism and cellular differentiation in response to changes in nutrient availability. Although the FoxO1 isoform is known to play a key role in adipogenesis, its physiological role in differentiated adipose tissue remains unclear.

Research Design And Methods: In this study, we analyzed the phenotype of FoxO1 haploinsufficient mice to investigate the role of FoxO1 in high-fat diet-induced obesity and adipose tissue metabolism.

Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation.

The transcription factors Foxo1, Foxo3 and Foxo4 modulate cell fate 'decisions' in diverse systems. Here we show that Foxo1-dependent gene expression was critical at many stages of B cell differentiation. Early deletion of Foxo1 caused a substantial block at the pro-B cell stage due to a failure to express interleukin 7 receptor-alpha.

Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor.

Human cancer cells frequently harbor chromosomal translocations that create chimeric fusion genes. The t(2;13) translocation is characteristic of the pediatric muscle tumor, alveolar rhabdomyosarcoma, and produces the chimeric transcription factor, PAX3-FOXO1, that contains the DNA binding elements of PAX3 and the transcriptional activation domain of FOXO1. Experiments designed to determine how PAX3-FOXO1 expression contributes to the development of muscle cell-derived tumors resulted in the discovery that the fusion protein misregulates gene expression and interrupts myogenic differentiation through a unique gain of function mechanism.

Genome-wide mapping and analysis of active promoters in mouse embryonic stem cells and adult organs.

By integrating genome-wide maps of RNA polymerase II (Polr2a) binding with gene expression data and H3ac and H3K4me3 profiles, we characterized promoters with enriched activity in mouse embryonic stem cells (mES) as well as adult brain, heart, kidney, and liver. We identified approximately 24,000 promoters across these samples, including 16,976 annotated mRNA 5' ends and 5153 additional sites validating cap-analysis of gene expression (CAGE) 5' end data. We showed that promoters with CpG islands are typically non-tissue specific, with the majority associated with Polr2a and the active chromatin modifications in nearly all the tissues examined.

PAX3-FOXO1 controls expression of the p57Kip2 cell-cycle regulator through degradation of EGR1.

The chimeric protein PAX3-FOXO1, resulting from a translocation between chromosomes 2 and 13, is the most common genetic aberration in the alveolar subtype of the human skeletal muscle tumor, rhabdomyosarcoma. To understand how PAX3-FOXO1 contributes to tumor development, we isolated and characterized muscle cells from transgenic mice expressing PAX3-FOXO1 under control of the PAX3 promoter. We demonstrate that these myoblasts are unable to complete myogenic differentiation because of an inability to up-regulate p57Kip2 transcription.

FoxOs in tumor suppression and stem cell maintenance.

The FoxO transcription factors have been implicated in many processes including tumor suppression and cell death. In this issue, two groups now report on mice that conditionally lack the three predominant FoxO transcription factors. Demonstrate that FoxOs are critical for the long-term maintenance of hematopoietic stem cells, and show that FoxOs suppress the formation of hemangiomas and lymphomas in mice.

Transgenic mice expressing PAX3-FKHR have multiple defects in muscle development, including ectopic skeletal myogenesis in the developing neural tube.

The t(2;13) chromosomal translocation is found in the majority of human alveolar rhabdomyosarcomas (RMS). The resulting PAX3-FKHR fusion protein contains PAX3 DNA-binding domains fused to the potent transactivation domain of FKHR, suggesting that PAX3-FKHR functions to deregulate PAX3-specific target genes and signaling pathways. We previously developed transgenic mice expressing PAX3-FKHR under the control of mouse Pax3 regulatory sequences to test this hypothesis.

Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer.

The FOXO family of transcription factors has been implicated in several cellular processes including cell cycle arrest, cell death and protection from stress stimuli. FOXO function is influenced by multiple signaling pathways. Many of these pathways are known to be misregulated in cancer.

Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass.

The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase.

FoxO: linking new signaling pathways.

Two recent reports reveal new roles for FoxO proteins in cell proliferation and tumorigenesis. Seoane and colleagues show that FoxO proteins play key roles in the TGFbeta-dependent activation of p21Cip1 by partnering with Smad3 and Smad4. FoxG1, a protein from a distinct Fox subfamily, binds FoxO/Smad complexes and blocks p21Cip1 expression.

FoxOs at the crossroads of cellular metabolism, differentiation, and transformation.

Forkhead transcription factors of the FoxO subfamily are emerging as a shared component among pathways regulating diverse cellular functions, such as differentiation, metabolism, proliferation, and survival. Their transcriptional output is controlled via a two-tiered mechanism of phosphorylation and acetylation. Modest alterations of this balance can result in profound effects.

Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification.

Genetic analysis in Caenorhabditis elegans has uncovered essential roles for DAF-16 in longevity, metabolism, and reproduction. The mammalian orthologs of DAF-16, the closely-related FOXO subclass of forkhead transcription factors (FKHR/FOXO1, FKHRL1/FOXO3a, and AFX/FOXO4), also have important roles in cell cycle arrest, apoptosis and stress responses in vitro, but their in vivo physiological roles are largely unknown. To elucidate their role in normal development and physiology, we disrupted each of the Foxo genes in mice.

The forkhead transcription factor Foxo1 regulates adipocyte differentiation.

An outstanding question in adipocyte biology is how hormonal cues are relayed to the nucleus to activate the transcriptional program that promotes adipogenesis. The forkhead transcription factor Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase.

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth.

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass.

Functional genomic comparison of lineage-related human bladder cancer cell lines with differing tumorigenic and metastatic potentials by spectral karyotyping, comparative genomic hybridization, and a novel method of positional expression profiling.

We have recently characterized T24T, an invasive and metastatic variant of the T24 human bladder cell line, resulting in a model for bladder cancer progression. To gain additional insight into the repertoire of genetic changes that may be responsible for the invasive and metastatic phenotype, we used spectral karyotyping (SKY) in combination with comparative genomic hybridization (CGH) in these cells. To assess the functional significance of the genetic differences found between the two cell lines, we have developed a positional expression profiling (PEP) method for comparing gene expression data obtained from oligonucleotide microarrays based upon chromosomal position.

Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.

Type 2 diabetes results from impaired action and secretion of insulin. It is not known whether the two defects share a common pathogenesis. We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes.

Analysis of the regulation of the A33 antigen gene reveals intestine-specific mechanisms of gene expression.

The A33 antigen is a transmembrane protein expressed almost exclusively by intestinal epithelial cells. The level of its expression is robust and uniform throughout the rostrocaudal axis of the human and mouse intestines. In the colon, strong expression is found in the basolateral membranes of both the proliferating cells in the lower regions of the crypts and the differentiating cells in the upper regions of crypts.