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At least 505 records · Page 28Linked to original sources
PubMed2005

Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization.

Forkhead box O (Foxo) transcription factors are emerging as critical transcriptional integrators among pathways regulating differentiation, proliferation, and survival, yet the role of the distinct Foxo family members in angiogenic activity of endothelial cells and postnatal vessel formation has not been studied. Here, we show that Foxo1 and Foxo3a are the most abundant Foxo isoforms in mature endothelial cells and that overexpression of constitutively active Foxo1 or Foxo3a, but not Foxo4, significantly inhibits endothelial cell migration and tube formation in vitro. Silencing of either Foxo1 or Foxo3a gene expression led to a profound increase in the migratory and sprout-forming capacity of endothelial cells. Gene expression profiling showed that Foxo1 and Foxo3a specifically regulate a nonredundant but overlapping set of angiogenesis- and vascular remodeling-related genes. Whereas angiopoietin 2 (Ang2) was exclusively regulated by Foxo1, eNOS, which is essential for postnatal neovascularization, was regulated by Foxo1 and Foxo3a. Consistent with these findings, constitutively active Foxo1 and Foxo3a repressed eNOS protein expression and bound to the eNOS promoter. In vivo, Foxo3a deficiency increased eNOS expression and enhanced postnatal vessel formation and maturation. Thus, our data suggest an important role for Foxo transcription factors in the regulation of vessel formation in the adult.

Animals↗
PubMed2006

Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization.

The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.

Apoptosis↗
PubMed2004

Expression and intracellular localization of FKHRL1 in mammary gland neoplasms.

FKHRL1 (FOXO3a), a member of the Forkhead family of genes, has been considered to be involved in the development of breast tumors; however, the in vivo expression and activation status of FKHRL1 in breast tumors still remains unclear. We immunohistochemically demonstrated the expression and intracellular localization of FKHRL1 in human breast tumors by the novel anti-FKHRL1 antibody which is available for formalin-fixed paraffin-embedded specimens. In a total of 51 cases of benign tumors, FKHRL1 was diffusely expressed in all cases, and its intracellular localization was revealed to be cytoplasmic (inactive form) in 94% of cases of intraductal papillomas (16/17) and 91% cases of fibroadenomas (31/34), with a similar pattern to normal glandular epithelium. In invasive ductal carcinomas, 83% of the cases (93/112) diffusely expressed FKHRL1; however, unlike benign tumors, 71% of the cases (66/93) showed the nuclear-targeted, active form of FKHRL1. Moreover, activated FKHRL1 was predominantly observed in scirrhous (29/36, 81% of the cases) and papillotubular (30/38, 79% of the cases) subtypes, compared to the solid-tubular subtype (7/19, 37% of the cases). Furthermore, the cases with nuclear-targeted FKHRL1 showed a tendency to have lymph nodal metastasis with statistical significance (P < 0.0001). Thus, the activation of FKHRL1 seems to be recognized as one of the specific features of invasive ductal carcinoma of the breast.

Adult↗
PubMed2002

Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons.

Cerebellar granule neurons depend on insulin-like growth factor-I (IGF-I) for their survival. However, the mechanism underlying the neuroprotective effects of IGF-I is presently unclear. Here we show that IGF-I protects granule neurons by suppressing key elements of the intrinsic (mitochondrial) death pathway. IGF-I blocked activation of the executioner caspase-3 and the intrinsic initiator caspase-9 in primary cerebellar granule neurons deprived of serum and depolarizing potassium. IGF-I inhibited cytochrome c release from mitochondria and prevented its redistribution to neuronal processes. The effects of IGF-I on cytochrome c release were not mediated by blockade of the mitochondrial permeability transition pore, because IGF-I failed to inhibit mitochondrial swelling or depolarization. In contrast, IGF-I blocked induction of the BH3-only Bcl-2 family member, Bim (Bcl-2 interacting mediator of cell death), a mediator of Bax-dependent cytochrome c release. The suppression of Bim expression by IGF-I did not involve inhibition of the c-Jun transcription factor. Instead, IGF-I prevented activation of the forkhead family member, FKHRL1, another transcriptional regulator of Bim. Finally, adenoviral-mediated expression of dominant-negative AKT activated FKHRL1 and induced expression of Bim. These data suggest that IGF-I signaling via AKT promotes survival of cerebellar granule neurons by blocking the FKHRL1-dependent transcription of Bim, a principal effector of the intrinsic death-signaling cascade.

Active Transport, Cell Nucleus↗
PubMed2026

Genome-Wide In Vivo RNAi Screening Identifies HOXD4 as a Tumor Metastasis Suppressor in Colorectal Cancer.

Metastasis remains a major therapeutic challenge in colorectal cancer, highlighting an urgent need to elucidate its underlying molecular mechanisms. In this study, an in vivo screening system integrating genome-wide short hairpin RNA library and next-generation sequencing identifies six candidate metastasis suppressors, among which Homeobox D4 (HOXD4) shows the most pronounced effects. Clinicopathological analyses reveal significant HOXD4 downregulation in tumor tissues relative to adjacent normal tissues, with reduced expression strongly correlating with aggressive tumor features. Functional assays demonstrate that HOXD4 depletion enhances migration, invasion, and tumorsphere formation in HCT116 cells, while ectopic HOXD4 overexpression reverses these malignant phenotypes in SW620 cells. Mechanistically, HOXD4 suppresses epithelial-mesenchymal transition (EMT) by directly binding to the promoter of Forkhead box Q1 (FOXQ1), a key driver of EMT and stemness, and thereby transcriptionally repressing its expression. Immunohistochemistry confirms an inverse correlation between HOXD4 and FOXQ1 expression in clinical specimens. Rescue experiments substantiate that HOXD4 exerts its metastasis-suppressing functions via FOXQ1 regulation. Collectively, these findings not only establish an efficient platform for screening tumor metastasis suppressors, but also identify HOXD4 as a master transcriptional regulator of the FOXQ1-EMT axis, providing a promising target for metastasis interception.

Humans↗
PubMed2002

Genes and translocations involved in POF.

Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Foxl2 and interacting proteins, or with defined changes in the X chromosome.

Chromosomes, Human, X↗
PubMed2002

Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.

We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.

Blepharophimosis↗
PubMed2004

Aging does not reduce the hepatocyte proliferative response of mice to the primary mitogen TCPOBOP.

It has been shown that the magnitude of DNA synthesis and the time at which maximal DNA synthesis occurs after two-thirds partial hepatectomy (PH) is greatly reduced in the liver of aged rodents compared to young animals. This reduction could represent an intrinsic defect in proliferation or a more specialized change in the response to PH. We therefore evaluated the proliferative capacity of hepatocytes in aged animals, following treatment with primary liver mitogens. We show that treatment of 12-month-old CD-1 mice with the hepatomitogen 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) caused an increase in hepatocyte proliferation similar to that seen in young (8-week-old) mice. The labeling index was 82% in the livers of aged mice versus 76% in young animals. Histological observation demonstrated that the number of hepatocytes entering mitoses was similar in both groups; the mitotic indices were 2.5 per thousand and 2.7 per thousand, respectively. Additional experiments showed that the timing of DNA synthesis and M phase were nearly identical in both aged and young mice. Stimulation of hepatocyte DNA synthesis was associated with increased expression of several cell cycle-associated proteins (cyclin D1, cyclin A, cyclin B1, E2F, pRb, and p107); all were comparable in aged mice and young mice. TCPOBOP treatment also increased expression of the Forkhead Box transcription factor m1b (Foxm1b) to a similar degree in both groups. In conclusion, hepatocytes retain their proliferative capacity in old age despite impaired liver regeneration. These findings suggest that therapeutic use of mitogens would alleviate the reduction in hepatocyte proliferation observed in the elderly.

Aging↗
PubMed2003

Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.

Bleparophimosis ptosis epicanthus inversus syndrome (BPES) is a rare disorder characterized by eyelid malformation and in some cases associated with premature ovarian failure. Although the familial form is autosomal dominant, many cases are also sporadic. The mutations causing this disorder were found in a winged/forkhead transcription factor gene named FOXL2. We have sequenced the mouse homolog for the FOXL2 gene and identified the Fugu rubripes (pufferfish) ortholog from the database. By alignment of the three sequences, we found an almost complete conservation of the forkhead domain in the three species. There is 95% and 61% conservation at the protein level between human-mouse and human-pufferfish, respectively. The polyalanine and polyproline tracts within the gene are absent in Fugu rubripes. An overview identifies four breaks in the conservation of the gene within these species. Using a direct sequencing approach, we performed mutation analysis from DNA of nine affected individuals from familial and sporadic cases. The mutations are distributed throughout the coding region of the FOXL2 gene. We identified five novel mutations: g.292delG (E19fsX149); g.530G>A (W98X); g.548A>G (H104R); g.652G>T (E139X); and g.1178_1185del8 (A314fsX530). In addition we also identified two known mutations g.823C>T (Q196X) and g.1092_1108dup17, the latter in individuals from three unrelated pedigrees.

Abnormalities, Multiple↗
PubMed2004

The human FOXL2 mutation database.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; MIM# 110100) is an autosomal dominant genetic condition in which an eyelid malformation is associated (type I) or not associated (type II) with premature ovarian failure (POF). In 2001, mutations in the FOXL2 gene, encoding a forkhead transcription factor, were shown to cause both BPES type I and II. Since then, a number of reports have appeared that describe intragenic FOXL2 mutations in BPES patients. In addition, a few FOXL2 variants have been reported in isolated POF patients and XX males. Previously, our group has described a large number of FOXL2 mutations, thereby demonstrating the existence of two mutational hotspots in FOXL2, intra- and interfamilial phenotypic variability in BPES families, and genotype-phenotype correlations for a number of mutations in BPES patients. Here we describe a locus-specific Human FOXL2 Mutation Database (http://medgen.ugent.be/foxl2/), created using the MuStaR software. Our database contains general information about the FOXL2 gene, as well as details about 135 intragenic mutations and variants of FOXL2, obtained from published papers, abstracts of meetings, and from unpublished data produced by our group. Not included in the current version of the database are variants residing outside the coding region of FOXL2 and molecular cytogenetic rearrangements of the FOXL2 locus. The Human FOXL2 Mutation Database was created to provide a unique publicly available online resource of information about human FOXL2 mutations/variants associated with BPES and POF. It allows remote users to submit new mutations to the database and to query the database using a web form. It will facilitate evaluation of the pathogenicity of a particular mutation, as it contains data about disease-causing mutations and polymorphisms in BPES and isolated POF patients, and a link to the known FOXL2 orthologs. Moreover, it will allow us to establish more accurate genotype-phenotype correlations, since clinical information is contained in the database.

Alleles↗
PubMed2001

Interferon-alpha promotes survival of human primary B-lymphocytes via phosphatidylinositol 3-kinase.

Signaling pathways for the antiviral and antiproliferative biological effects of type I interferons (IFN) are well established. In this report we demonstrate a novel signaling pathway for IFN-alpha, as it induced rapid phosphorylation of both PKB/Akt and its substrate forkhead. The PI3-kinase inhibitor LY294002 abolished these phosphorylations. PI3-kinase has been implicated in cell survival mediating its effect through the second messenger PIP3 and the subsequent activation of PKB/Akt. We could show that IFN-alpha inhibited spontaneous apoptosis of primary B-lymphocytes, in the absence of a mitogenic stimulus. This effect was inhibited by LY294002. Thus, our data suggests that IFN-alpha promotes survival of peripheral B-lymphocytes via the PI3-kinase-PKB/Akt pathway. In addition, IFN-alpha stimulation of anti-IgM activated cells resulted in downregulated expression of the cell cycle inhibitor p27/Kip1.

Apoptosis↗
PubMed2006

A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.

The blepharophimosis syndrome (BPES) is an autosomal dominant developmental disorder in which craniofacial/eyelid malformations are associated (type I) or not (type II) with premature ovarian failure (POF). Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for both types of BPES. Heterozygous polyalanine expansions of +10 residues (FOXL2-Ala24) account for 30% of FOXL2 mutations and are fully penetrant for the eyelid phenotype. Here we describe the first homozygous FOXL2 mutation leading to a polyalanine expansion of +5 residues (FOXL2-Ala19). This novel mutation segregates in an Indian family where heterozygous mutation carriers are unaffected whereas homozygous individuals have the typical BPES phenotype, with proven POF in one female. Expression of the FOXL2-Ala19 protein in COS-7 cells revealed a significantly higher cytoplasmic retention compared to the wild-type protein. This is the first study providing genetic evidence for a recessive inheritance of BPES associated with ovarian dysfunction.

Adult↗
PubMed2004

Intracellular mechanisms mediating the anti-apoptotic action of gastrin.

We previously reported that gastrin (G17) inhibits apoptosis of AR4-2J pancreatic adenocarcinoma cells, through the activation of Akt. We dissected the mechanisms responsible for this effect. D2, a CCKB receptor antagonist, inhibited G17 induction of Akt phosphorylation, measured by Western blots with anti-phospho-Akt antibodies. The intracellular calcium chelator BAPTA-AM, but not the PKC inhibitor GF109203X, blocked G17 induction of Akt. G17 stimulated BAD phosphorylation, measured by both Western blots with anti-phospho-BAD antibodies and by in vitro Akt kinase assays using recombinant BAD as substrate. G17 also induced FOXO3 phosphorylation assessed by Western blots with anti-phospho-FOXO3 antibodies, and BAPTA-AM inhibited this effect. Gastrin inhibited luciferase activity in cells transfected with FOXO1 together with a vector containing insulin-responsive sequences upstream of the luciferase reporter gene. In conclusion, G17 induces Akt through activation of CCKB receptors and of intracellular calcium-dependent, PKC-independent, pathways. This effect leads to BAD phosphorylation and to forkhead transcription factors inactivation.

Animals↗
PubMed2005

Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis.

Blepharophimosis-ptosis-epicanthus inversus syndrome type I is an autosomal disorder caused by mutations in FOXL2 gene and associated with premature ovarian failure in women by a dominant inheritance. FOXL2 is a recently identified protein that belongs to forkhead family transcription factor, of which signaling pathways are still unknown. Here, we show that FOXL2 induces apoptosis in both Chinese hamster ovary cells and rat granulosa cells, and it interacts with DP103, a DEAD box-containing protein. Overexpression of DP103 itself did not affect cell viability while its coexpression with FOXL2 led to the potentiation of cell death. Our results present previously undiscovered functions of these proteins, an apoptotic activity of FOXL2 in the ovary and a modulating activity of DP103 by interacting with FOXL2.

Animals↗
PubMed2006

Insulin downregulates angiopoietin-like protein 4 mRNA in 3T3-L1 adipocytes.

Angiopoietin-like protein 4 (angptl4) is mainly secreted from adipose tissue and inhibits lipoprotein lipase activity. The expression and plasma levels of angptl4 are increased by fasting. To clarify its regulation in diabetes and metabolic syndrome, we investigated the effect of insulin on angptl4 mRNA expression in 3T3-L1 adipocytes by using quantitative real-time PCR. Insulin suppressed angptl4 mRNA expression in time- and dose-dependent manners, and the inhibitory effect was attenuated by a RNA synthesis inhibitor actinomycin D and a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Adenoviral-mediated overexpression of forkhead transcription factor Foxo1 increased angptl4 mRNA expression, and insulin significantly suppressed its effect. In addition, insulin failed to decrease angptl4 mRNA expression in an insulin-resistant state induced by TNF-alpha in 3T3-L1 adipocytes. These results suggest that insulin downregulates angptl4 mRNA expression via PI3K/Foxo1 pathway in 3T3-L1 adipocytes, and that the reduction of angptl4 mRNA by insulin is attenuated in insulin resistance.

3T3-L1 Cells↗
PubMed2006

Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model.

Lithium used in bipolar mood disorder therapy protects neurons from brain ischemic cell death. Here, we documented that lithium administration under microsphere-embolism (ME)-induced brain ischemia restored decreased protein kinase B (Akt) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activities 24 h after ischemia in rat brain. Akt activation was associated with increased phosphorylation of its potential targets forkhead transcription factor (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). In parallel with decreased CaMKII autophosphorylation, we also found marked dephosphorylation of tau proteins 24-72 h after ME. Increased protein phosphatase 2A (PP2A) activity was found 24 h after ME. Inhibition of increased PP2A activity by lithium treatment apparently mediated restored tau phosphorylation. Taken together, activation of Akt and CaMKII by lithium was associated with neuroprotective activity in ME-induced neuronal injury.

Animals↗
PubMed2006

A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.

Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.

14-3-3 Proteins↗
PubMed2005

FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction.

Diabetes causes pancreatic beta cell failure through hyperglycemia-induced oxidative stress, or "glucose toxicity." We show that the forkhead protein FoxO1 protects beta cells against oxidative stress by forming a complex with the promyelocytic leukemia protein Pml and the NAD-dependent deacetylase Sirt1 to activate expression of NeuroD and MafA, two Insulin2 (Ins2) gene transcription factors. Using acetylation-defective and acetylation-mimicking mutants, we demonstrate that acetylation targets FoxO1 to Pml and prevents ubiquitin-dependent degradation. We show that hyperglycemia suppresses MafA expression in vivo and that MafA inhibition can be prevented by transgenic expression of constitutively nuclear FoxO1 in beta cells. The findings provide a mechanism linking glucose- and growth factor receptor-activated pathways to protect beta cells against oxidative damage via FoxO proteins.

Acetylation↗