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PubMed2005

Genomic inventory and expression of Sox and Fox genes in the cnidarian Nematostella vectensis.

The Sox and Forkhead (Fox) gene families are comprised of transcription factors that play important roles in a variety of developmental processes, including germ layer specification, gastrulation, cell fate determination, and morphogenesis. Both the Sox and Fox gene families are divided into subgroups based on the amino acid sequence of their respective DNA-binding domains, the high-mobility group (HMG) box (Sox genes) or Forkhead domain (Fox genes). Utilizing the draft genome sequence of the cnidarian Nematostella vectensis, we examined the genomic complement of Sox and Fox genes in this organism to gain insight into the nature of these gene families in a basal metazoan. We identified 14 Sox genes and 15 Fox genes in Nematostella and conducted a Bayesian phylogenetic analysis comparing HMG box and Forkhead domain sequences from Nematostella with diverse taxa. We found that the majority of bilaterian Sox groups have clear Nematostella orthologs, while only a minority of Fox groups are represented, suggesting that the evolutionary pressures driving the diversification of these gene families may be distinct from one another. In addition, we examined the expression of a subset of these genes during development in Nematostella and found that some of these genes are expressed in patterns consistent with roles in germ layer specification and the regulation of cellular behaviors important for gastrulation. The diversity of expression patterns among members of these gene families in Nematostella reinforces the notion that despite their relatively simple morphology, cnidarians possess much of the molecular complexity observed in bilaterian taxa.

Amino Acid Sequence↗
PubMed1998

The mouse Fkh1/Mf1 gene: cDNA sequence, chromosomal localization and expression in adult tissues.

The 'winged helix' or 'forkhead' transcription factor gene family is defined by a common 100-amino-acid DNA-binding motif. Here, we describe the chromosomal position, start site of transcription, sequence and adult expression pattern of the mouse Fkh1/Mf1 (Forkhead homologue 1/mesoderm/mesenchyme forkhead 1) gene. This gene contains one exon and encodes a protein of 553 amino acids that is highly related to the mouse MFH1 protein. The Fkh1/Mf1 mRNA is expressed widely in adult tissues. Linkage analysis showed that the Fkh1/Mf1 gene is localized to chromosome 13 at 17.02cM from the centromer, in close proximity to Bmp6 and Hfh1, another distinct member of the winged helix gene family.

Amino Acid Sequence↗
PubMed1997

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23).

We report the cloning and characterization of the entire AFX gene which fuses to MLL in acute leukemias with a t(X;ll)(q13;q23). AFX consists of two exons and encodes for a protein of 501 amino acids. We found that normal B- and T-cells contain similar levels of AFX mRNA and that both the MLL/AFX as well as the AFX/MLL fusion transcripts are present in the cell line and the ANLL sample with a t(X;11)(q13;q23). The single intron of the AFX gene consists of 3706 nucleotides. It contains five simple sequence repeats with lengths of at least 12 bps, a chi-like octamer sequence (GCA/TGGA/TGG) and several immunoglobulin heptamer-like sequences (GATAGTG) that are distributed throughout the entire AFX intron sequence. In the KARPAS 45 cell line the breakpoints occur at nucleotides 2913/2914 of the AFX intron and at nucleotides 4900/4901 of the breakpoint cluster region of the MLL gene. The AFX protein belongs to the forkhead protein family. It is highly homologous to the human FKHR protein, the gene of which is disrupted by the t(2;13)(q35;q14), a chromosome rearrangement characteristic of alveolar rhabdomyosarcomas. It is noteworthy that the t(X;11)(q13;q23) in the KARPAS 45 cell line and in one acute nonlymphoblastic leukemia (ANLL) disrupts the forkhead domain of the AFX protein exactly at the same amino acids as does the t(2;13)(q35;q14) in case of the FKHR protein. In addition, the 5'-part of the AFX protein contains a conserved hexapeptide motif (QIYEWM) that is homologous to the functionally important conserved hexapeptide QIYPWM upstream of the homeobox domain in Hox proteins. This motif mediates the co-operative DNA binding of Pbx family members and Hox proteins and, therefore, plays an important role in physiologic and oncogenic processes. In acute leukemias with a t(X;11)(q13;q23), this hexapeptide motif is separated from the remaining forkhead domain within the AFX protein. The predicted amino acid sequence of AFX differs significantly from the partial AFX protein sequence published previously (Genes, Chromosomes and Cancer, 1994, 11, 79-84). This discrepancy can be explained by the occurrence of two sequencing errors in the earlier work at nucleotide number 783 and 844 (loss of a cytosine residue or guanosine residue, respectively) that lead to two reading frame shifts.

Acute Disease↗
PubMed2005

FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.

Forkhead members of the 'O' class (FoxO) are transcription factors crucial for the regulation of metabolism, cell cycle, cell death and cell survival. FoxO factors are regulated by insulin-mediated activation of PI3K (phosphoinositide 3-kinase)-PKB (protein kinase B) signalling. Activation of PI3K-PKB signalling results in the phosphorylation of FoxO factors on three conserved phosphorylation motifs, which are essential for the translocation of FoxO factors from the nucleus to the cytosol. FoxO6, however, remains mostly nuclear due to the fact that its shuttling ability is dramatically impaired. FoxO1, FoxO3 and FoxO4 all contain an N- and C-terminal PKB motif and a motif located in the forkhead domain. FoxO6 lacks the conserved C-terminal PKB motif, which is the cause of the shuttling impairment. Since FoxO6 can be considered constitutively nuclear, we investigated whether it is also a constitutively active transcription factor. Our results show that FoxO6 transcriptional activity is inhibited by growth factors, independent of shuttling, indicating that it is not constitutively active. The PKB site in the forkhead domain (Ser184) regulated the DNA binding characteristics and the N-terminal PKB site acted as a growth factor sensor. In summary, FoxO6 is not a constitutively active transcription factor and can be regulated by growth factors in a Thr26- and Ser184-dependent manner, independent of shuttling to the cytosol.

Amino Acid Motifs↗
PubMed2003

Mechanosensitive p27Kip1 regulation and cell cycle entry in vascular smooth muscle cells.

BACKGROUND: Cyclic stretch plays an important role in the homeostasis of vessel structure. Increased forces might, however, contribute to remodeling processes, resulting in vascular proliferative diseases. The initial molecular events necessary for mechanosensitive cell cycle entry of quiescent smooth muscle cells are poorly understood. METHODS AND RESULTS: In this study, we demonstrate that mechanical strain resulted in a rapid, integrin-dependent but mitogen-independent activation of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) in quiescent vascular smooth muscle cells. Subsequently, downstream ALL 1 fused gene from chromosome X (AFX)-like forkhead transcription factors were inactivated, leading to transcriptional downregulation of p27Kip1. This contrasted with the posttranscriptional protein reduction of p27Kip1 in cells stimulated with serum mitogens. Stretch-mediated p27Kip1 downregulation was accompanied by activation of cyclin-dependent kinase 2, hyperphosphorylation of retinoblastoma protein, and proliferation. Forkhead transcription factor inactivation and p27Kip1 downregulation were prevented by the PI3-K inhibitors wortmannin and LY294002. Pharmacological blockade of other kinases, such as p42/44, p38, and protein kinase A or C, did not influence the mechanosensitive gene regulation. p27Kip1 downregulation and cell cycle entry were, however, prevented by overexpression of a constitutively inactive form of Akt or constitutively active forms of forkhead transcription factors. CONCLUSIONS: Our data demonstrate that the earliest cell cycle events can occur in a solely mechanosensitive fashion. Vascular smooth muscle cells are, furthermore, able to use transcriptional or posttranscriptional mechanisms to regulate p27Kip1, depending on the stimulus to which they are exposed. This observation has novel implications for understanding of vascular proliferative diseases.

Animals↗
PubMed1993

Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm.

The HNF-3 alpha, beta and gamma genes constitute a family of transcription factors that are required for hepatocyte-specific gene expression of a number of genes, e.g. transthyretin, alpha-1 antitrypsin and tyrosine aminotransferase. These genes share a highly conserved DNA-binding domain first found in the Drosophila gene, forkhead, which is required for the normal patterning of the developing gut and central nervous system in Drosophila. In adult mouse tissues, transcripts from HNF-3 alpha and beta have been localised to the liver, intestine and lung, whereas HNF-3 gamma is found in the liver, intestine and testis. In light of the early developmental significance of forkhead in Drosophila, we have compared the patterns of expression of HNF-3 alpha, beta and gamma mRNAs during murine embryogenesis. We find that these genes are sequentially activated during development in the definitive endoderm. HNF-3 beta mRNA is expressed in the node at the anterior end of the primitive streak in all three germ layers and is the first gene of this family to be activated. Subsequently, HNF-3 alpha is transcribed in the primitive endoderm in the region of the invaginating foregut and HNF-3 gamma appears upon hindgut differentiation. These genes have different anterior boundaries of mRNA expression in the developing endoderm and transcripts are found in all endoderm-derived structures that differentiate posterior to this boundary. Therefore, we propose that these genes define regionalization within the definitive endoderm. Furthermore, differential mRNA expression of HNF-3 alpha and beta is detected in cells of the ventral neural epithelium, chordamesoderm and notochord. In the neural epithelium, expression of HNF-3 alpha and beta mRNA becomes localised to cells of the floor plate. We propose that, in addition to their characterised requirement for liver-specific gene expression, HNF-3 alpha and beta are required for mesoderm and neural axis formation. We also conclude that HNF-3 beta is the true orthologue of the Drosophila forkhead gene.

Animals↗
PubMed2004

Fkh2p and Sep1p regulate mitotic gene transcription in fission yeast.

In the fission yeast Schizosaccharomyces pombe, several genes including cdc15+, spo12+, fin1+, slp1+, ace2+ and plo1+ are periodically expressed during M phase. The products of these genes control various aspects of cell cycle progression including sister chromatid separation, septation and cytokinesis. We demonstrate that periodic expression of these genes is regulated by a common promoter sequence element, named a PCB. In a genetic screen for cell cycle regulators we have identified a novel forkhead transcription factor, Fkh2p, which is periodically phosphorylated in M phase. We show that Fhk2p and another forkhead transcription factor, Sep1p, are necessary for PCB-driven M-phase-specific transcription. In a previous report we identified a complex by electrophoretic mobility shift assay, which we termed PBF, that binds to a 150 bp region of the cdc15+ promoter that contains the PCB element. We have identified Mbx1p, a novel MADS box protein, as a component of PBF. However, although Mbx1p is periodically phosphorylated in M phase, Mbx1p is not required for periodic gene transcription in M phase. Moreover, although PBF is absent in strains bearing a C-terminal epitope tag on Fkh2p, simultaneous deletion of fkh2+ and sep1+ does not abolish PBF binding activity. This suggests that Mbx1p binds to gene promoters, but is not required for transcriptional activation. Together these results suggest that the activation of the Fkh2p and Sep1p forkhead transcription factors triggers mitotic gene transcription in fission yeast.

Cell Cycle Proteins↗
PubMed2006

K+ regulates DNA binding of transcription factors to control gene expression related to neuronal apoptosis.

The loss of intracellular K+ promotes neuronal apoptosis. The mechanism by which K+ acts on apoptosis, however, remains largely unknown. Here we showed that K+ selectively affects DNA binding activity of transcriptional factors in vitro. Low K+ concentration ([K+]) promoted the DNA binding activity of p53 and Forkhead, proapoptotic transcriptional factors, whereas it inhibited that of cAMP-responsive element-binding protein, an anti-apoptotic transcriptional factor. In contrast, K+ did not affect the DNA binding activity of Ying Yang 1, CCAAT/enhancer binding protein and early growth response protein-1. The expression of bax and bim, proapoptotic genes known to be regulated by p53 and Forkhead, respectively, was enhanced in cortical neurons deprived of serum, a condition known to cause K+ loss, whereas the expression of c-fos, a cAMP-responsive element-binding protein target gene, was inhibited. Furthermore, blocking K+ channels suppressed the enhancement of bim mRNA level and the reduction of c-fos mRNA level induced by K+ loss, whereas it had no effect on the stimulation of Forkhead or cAMP-responsive element-binding protein induced by K+ loss. These results suggest that low intracellular [K+] selectively affects DNA binding activity of transcriptional factors to regulate gene expression related to neuronal apoptosis.

Animals↗
PubMed2006

Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis.

Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Balpha (PKBalpha), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase-activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.

Alkaloids↗
PubMed2005

Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain.

In order to obtain leads to molecular mechanisms of signal transduction pathways and controlled gene expression in neuronal development we have screened the adult mouse brain for expressed forkhead transcription factors using a degenerate RT-PCR approach. Here, we focus on three FoxO genes found to be expressed in the brain: FoxO1, FoxO3 and FoxO6. The FoxO subfamily of forkhead transcription family is emerging as a central keypoint in an array of cellular functions, such as metabolism, differentiation and transformation. In situ hybridization experiments on adult and embryonic mouse brain showed differential expression patterns for three FoxO members. FoxO1 was strongly expressed in the striatum and neuronal subsets of the hippocampus (dentate gyrus and the ventral/posterior part of the CA regions), whereas FoxO3 was more diffusely expressed throughout the brain including all hippocampal areas, cortex and cerebellum. FoxO6 expression was eminent in various parts of the adult mouse brain, including the entire hippocampus, the amygdalohippocampal area and the shell of the nucleus accumbens. Remarkably, all three FoxO transcription factors were expressed relatively late in the developing murine brain, starting between E12.5 and E14. In summary, the presented data show FoxO factors to be expressed in the adult and developing mouse brain, in a spatially end temporally restricted manner.

Animals↗
PubMed2000

Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues.

daf-16 is a forkhead-type transcription factor, functioning downstream of insulin-like signals, and is known to be critical to the regulation of life span in Caenorhabditis elegans. Mammalian DAF-16 homologues include AFX, FKHR and FKHRL1, which contain a conserved forkhead domain and three putative phosphorylation sites for the Ser/Thr kinase Akt/protein kinase B (PKB), as well as for DAF-16. To assess the function of the homologues, we examined tissue distribution patterns of mRNAs for DAF-16 homologues in mice. In the embryos, expressions of AFX, FKHR and FKHRL1 mRNAs were complementary to each other and were highest in muscle, adipose tissue and embryonic liver. The characteristic expression pattern remained in the adult, except that signals of FKHRL1 became evident in more tissues, including the brain. In order to clarify whether each DAF-16 homologue had different target genes, we determined the consensus sequences for the binding of DAF-16 and the mouse homologues. The binding sequences for all four proteins shared a core sequence, TTGTTTAC, daf-16 family protein-binding element (DBE) binding protein. However, electrophoretic mobility shift assay showed that the binding affinity of DAF-16 homologues to the core sequence was stronger than that to the insulin-responsive element in the insulin-like growth factor binding protein-1 promoter region, which has been identified as a binding sequence for them. We identified one copy of the DBE upstream of the first exon of sod-3 by searching the genomic database of C. elegans. Taken together, DAF-16 homologues can fundamentally regulate the common target genes in insulin-responsive tissues and the specificity to target genes of each protein is partially determined by the differences in their expression patterns.

Alternative Splicing↗
PubMed2002

FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling.

We report that the Forkhead family of transcription factors, FKHRL1, FKHR and AFX are novel components of neurotrophin receptor signaling. NGF rapidly induced the phosphorylation of FKHRL1 in PC12 cells. This effect is mediated by high-affinity TrkA receptor as nerve growth factor (NGF) induced the phosphorylation of FKHRL1 only in TrkA expressing cells and not p75-expressing cells. Additional experiments with various kinase inhibitors, the transient expression of constitutively active and dominant-negative Akt, and in vitro kinase assay revealed that phosphatidylinositol-3 (PtdIns3)/Akt kinase mediated the actions of NGF. Similar data were obtained for brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in primary cortical cultured neurons. These findings demonstrate for the first time that the phosphorylation of the Forkhead family of transcription factors can be modulated by neurotrophins via Trk receptors and PtdIns3K/Akt kinase (but not MAP or S6p70 kinases) in neuronal and non-neuronal cells. Moreover, survival assays with the PtdIns3 kinase inhibitor LY294002, active and dominant-negative forms of Akt indicate that the phosphorylation of FKHRL1 plays a role in neurotrophins-mediated cell survival.

3T3 Cells↗
PubMed2003

FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.

Forkhead transcription factors of the FoxO-group are associated with cellular processes like cell cycle progression and DNA-repair. FoxO function is regulated by protein kinase B (PKB) via the phosphatidylinositol 3-kinase/PKB survival pathway. Phosphorylation of serine and threonine residues in specific PKB phosphorylation motifs leads to exclusion of FoxO-proteins from the nucleus, which excludes them from exerting transactivating activity. Members of the FoxO-group have three highly conserved regions containing a PKB phosphorylation motif. This study describes the cloning and characterization of a novel forkhead domain gene from mouse that appeared to be highly related to the FoxO group of transcription factors and was therefore designated FoxO6. The FoxO6 gene was mapped in region D1 on mouse chromosome 4. In humans, FOXO6 is located on chromosomal region 1p34.1. Embryonic expression of FoxO6 is most apparent in the developing brain, and FoxO6 is expressed in a specific temporal and spatial pattern. Therefore it is probably involved in regulation of specific cellular differentiation. In the adult animal FoxO6 expression is maintained in areas of the nucleus accumbens, cingulate cortex, parts of the amygdala, and in the hippocampus. Structure function analysis of FoxO6 compared with its group members shows that the overall homology is high, but surprisingly a highly conserved region containing multiple phosphorylation sites is lacking. In transfection studies, FoxO6 coupled to GFP showed an unexpected high nuclear localization after stimulation with growth factors, in contrast to the predominant cytosolic localization of FoxO1 and FoxO3. We also show that nuclear export of FoxO6 is mediated through the phosphatidylinositol 3-kinase/PKB pathway. Furthermore, we show using a chimeric approach that we can fully restore the ability of FoxO6 to shuttle between nucleus and cytosol. In conclusion, the data presented here gives a new view on regulation of FoxO-function through multiple phosphorylation events and other mechanisms involved in the nuclear exclusion of FoxO-proteins.

Amino Acid Motifs↗
PubMed2003

FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons.

Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal-induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation-induced death of sympathetic neurons.

Animals↗
PubMed2004

GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal-induced apoptosis.

Interleukin-2 (IL-2) withdrawal is a physiologic process inducing cell death in activated T lymphocytes. Glucocorticoid-induced leucine zipper (GILZ) has recently been identified as a protein modulating T-cell receptor activation by repressing various signaling pathways. We report here that IL-2 deprivation leads to expression of GILZ in T lymphocytes. We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal. To assess the functional consequences of this induction, we used 2 strategies, GILZ overexpression and GILZ silencing in murine IL-2-dependent CTLL-2 cells. GILZ overexpression protects CTLL-2 cells from IL-2 withdrawal-induced apoptosis, whereas cell death is accelerated in cells unable to express GILZ. Concomitantly, the expression of Bim is inhibited in GILZ-overexpressing cells and enhanced when GILZ expression is impaired. Furthermore, GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim expression but also to down-regulation of GILZ itself. Therefore, GILZ is a transiently expressed protein induced upon IL-2 withdrawal that protects T cells from the onset of apoptosis.

Animals↗
PubMed2003

FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients.

Mutations in the forkhead transcription factor gene 2 (FOXL2) were recently reported to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II. Evidence was provided that BPES type I (eyelid abnormalities and female infertility) is caused by mutations resulting in a truncated FOXL2 protein. In contrast, mutant FOXL2 proteins, either with inserted aminoacids in the forkhead domain or polyalanine tract, or with novel aminoacids at the carboxyl end, were found in BPES type II, in which fertility is generally normal. We report a 32-year-old female patient with sporadic BPES and a history of menstrual cycle irregularities and periods of secondary amenorrhoea. A heterozygous frameshift mutation (c959-960insG) was found in the FOXL2 gene, resulting in a predicted FOXL2 protein with 212 novel aminoacids in the carboxyl end, suggesting BPES type II despite menstrual irregularities. The clinical presentations of our patient and of three female patients with BPES type II in the report of De Baere et al. [2001: Hum Mol Genet 10:1591-1600.] indicate phenotypic overlap between BPES type I and II. These observations do not support a clear-cut prediction of female fertility based on the FOXL2 molecular defect. As a consequence, FOXL2 mutation testing in female patients of child-bearing age with BPES should be handled with caution, and a two-step genetic counseling approach, including an initial pre-test information session, is proposed.

Abnormalities, Multiple↗
PubMed2006

FoxM1: at the crossroads of ageing and cancer.

Forkhead transcription factors are intimately involved in the regulation of organismal development, cell differentiation and proliferation. Here we review the current knowledge of the role played by FoxM1 in these various processes. This particular member of the Forkhead family is broadly expressed in actively dividing cells and is crucial for cell cycle-dependent gene expression in the G2 phase of the cell cycle. FoxM1 plays a crucial role in insuring the fidelity of the cell division process, as inhibition of FoxM1 activity results in serious aberrancies during mitosis, such as frequent chromosome missegregation, defects in cytokinesis and overt aneuploidy. FoxM1 expression also appears to be tightly correlated with the proliferative rate of a cell. For example, FoxM1 is one of the most significantly down-regulated genes in prematurely aged human fibroblasts (Progeria syndrome), while elevated expression of FoxM1 is seen in most human carcinomas. These observations suggest that interference with FoxM1 activity may contribute to the increase in mitotic errors seen in human diseases such as cancer and early onset of ageing diseases. In this review, several aspects of FoxM1 function will be discussed, as well as their implication in tumorigenesis.

Aging↗
PubMed2004

FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO3.

Proliferation, differentiation, and survival of hematopoietic cells are regulated by cytokines, acting through specific receptors. FLT3 ligand (FL) is one of the most important cytokines for regulation of the hematopoietic system, and its receptor FLT3 is expressed on both stem cells and progenitors. Regulation of Forkhead transcription factors has been described as an important mechanism to control apoptosis and cell cycle progression in hematopoietic progenitors. Here we report that FL induces AKT/PKB activation, which in turn phosphorylates and thereby inactivates the Forkhead protein FoxO3 in the progenitor cell line FDC-P1 stably expressing murine FLT3 receptor. Phosphorylation of AKT and FoxO3 was blocked by the PI-3 kinase inhibitor LY294002 but not by the MAP kinase inhibitor PD98059. Expression of a mutated FoxO3, in which all three inhibitory phosphorylation sites were mutated to alanine, led to rapid increase of apoptotic cells in the presence of FL. These results suggest that FL-induced regulation of apoptosis is executed by FoxO3.

Animals↗