Disease relevance of FOXO1

• In addition, FOXO1A was transcriptionally down-regulated in some prostate cancers [1].
• Human endometrial fibroblasts (HuF) expressed FOXO1A, progesterone receptor A (PGRA), and progesterone receptor B (PGRB) proteins, whereas the endometrial adenocarcinoma cell line, HEC-1B cells, expressed only FOXO1A and no detectable PGR proteins [2].
• Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed [3].
• We determined whether expression of Pax3-FKHR in the mouse germ line would render these animals prone to the development of rhabdomyosarcomas [4].
• Since Pax3 induced a mesenchymal to epithelial transition (MET) in human SaOS-2 osteosarcomas, we hypothesized that Pax3/FKHR would also induce a morphological change in SaOS-2 cells [5].
• Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer [6].
• The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low [7].

Psychiatry related information on FOXO1

• Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures [8].

High impact information on FOXO1

• In C. elegans, removing the germ cells extends life span by triggering the nuclear localization and activation of the DAF-16/FOXO transcription factor in the intestine [9].
• Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting [10].
• Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction [10].
• These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions [11].
• Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated [11].

Chemical compound and disease context of FOXO1

• The effect of H(2)O(2) on downstream Akt targets was examined by Western blot using antibody against phosphorylated forkhead in rhabdomyosarcoma (FKHR) and phosphorylated glycogen synthase kinase (GSK)-3beta [12].
• Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells [13].
• Intracerebroventricular injection of orthovanadate 30 minutes before ischemia inhibited dephosphorylation of FKHR after reperfusion, and blocked delayed neuronal death in the CA1 region [14].
• To the extent that this model reflects human disease, these data suggest that FOXO function may be compromised with androgen-independent progression of human prostate cancer [15].

Biological context of FOXO1

• Functionally, ectopic expression of FOXO1A inhibited, and its knockdown promoted, cell proliferation or survival [1].
• Consistent with the understanding of FOXO1A biology, our findings suggest that FOXO1A is the 13q14 tumor suppressor gene, at least in prostate cancer [1].
• Overexpressing FOXO1A also caused a change in cell shape, in that the stromal fibroblasts acquired a rounded, epithelioid appearance [16].
• When FOXO1A expression was silenced using small interference RNA, IGFBP1 expression decreased in both HuF and HEC-1B cells [2].
• The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic beta-cell genes including IPF1 [17].

Anatomical context of FOXO1

• Deletion at FOXO1A was detected in 31% to 34% in 6 cell lines, 27 xenografts, and 72 clinical specimens of prostate cancer, and was significantly more frequent than deletions at surrounding loci [1].
• FKHR, a FOXO forkhead transcription factor, stimulates IGFBP-1 promoter activity in liver cells through the insulin response sequences (IRSs) [18].
• Here we show that FKHR and HOXA10 are expressed in baboon endometrium during the menstrual cycle and pregnancy [18].
• Among metastatic ARMS, bone marrow involvement was significantly higher in PAX3-FKHR-positive patients [19].
• Similarly, SH2-Bbeta stimulated the accumulation of FKHR in the cytoplasm of 293T and COS-7 cells, whereas SH2-Bbeta(R555E) enhanced its accumulation in the nucleus [20].

Associations of FOXO1 with chemical compounds

• Furthermore, FOXO1A inhibited androgen- and androgen receptor-mediated gene regulation and cell proliferation [1].
• Reporter studies demonstrated that whereas liganded PGRA or PGRB increased a progesterone response element-linked reporter construct, pPRE/ GRE.E1b.Luc, coexpression of FOXO1A inhibited the PGRB response in HuF and synergistically increased PGRA and PGRB response in HEC-1B cells [2].
• The ER alpha-FKHR interaction depends on beta-estradiol and is reduced significantly in the absence of hormone or the presence of Tamoxifen [21].
• The FKHR interaction was specific to ER alpha and was not detected with other ligand-activated steroid receptors [21].
• Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors [22].
• IGF1 or insulin abolish the Foxo1 occupancy of these promoters [23].

Physical interactions of FOXO1

• Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad [24].
• The t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma tumors (ARMS) creates an oncogenic transcriptional activator by fusion of PAX3 DNA binding motifs to a COOH-terminal activation domain derived from the FKHR gene [25].
• We find that FKHR can bind in vitro to the insulin-responsive sequence (IRS) in the insulin-like growth factor-binding protein 1 promoter and can activate transcription from a reporter plasmid containing multiple copies of the IRS [26].
• FKHR interacted with the DNA binding domain of HNF-4 and inhibited HNF-4 binding to the cognate DNA [27].

Enzymatic interactions of FOXO1

• These experiments suggest that DYRK1A may phosphorylate FKHR at Ser(329) in vivo [28].
• FKHR is phosphorylated by protein kinase B (PKB) at Thr24, Ser256 and Ser319 in response to growth factors, stimulating the nuclear exit and inactivation of this transcription factor [29].
• CDK2 specifically phosphorylated FOXO1 at serine-249 (Ser(249)) in vitro and in vivo [30].
• Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells [31].
• Furthermore, the binding affinity of HNF-4 with phosphorylated FKHR significantly decreased in comparison to that with unphosphorylated FKHR [27].

Regulatory relationships of FOXO1

• Conversely, ER alpha repressed FKHR-mediated transactivation through an insulin response sequence, and cell cycle arrest induced by FKHRL1 in MCF7 cells was abrogated by estradiol [21].
• We demonstrate here that Pax3/FKHR more potently induces a MET in SaOS-2 cells than Pax3 [5].
• Reporter gene studies reveal that FKHR stimulates both baboon and human IGFBP-1 promoter activity, whereas HOXA10 alone has a relatively weak effect [18].
• These results indicate that TNF induces activation of the FOXO1 transcription factor, which acts as a master switch to control apoptosis [32].
• Our results indicated that the interaction of FKHR with 14-3-3 proteins was not required for IGF-1-stimulated exclusion of FKHR from the nucleus [33].
• Ectopic FOXO3 activation blocked the proliferation of fibroblasts and induced the expression of FOXO1, FOXO4, and p27-KIP1 [34].
• MDM2 promotes the ubiquitination of FOXO1 in a cell-free system, and its knockdown by small interfering RNA causes accumulation of endogenous FOXO3A protein in cells and enhances the expression of FOXO target genes [35].

Other interactions of FOXO1

• Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown [4].
• Insulin suppresses the hPDK4 induction by glucocorticoids through inactivation of the FOXO factors [22].
• TIMP3 and CNR1 levels decreased even further in response to H+dbcAMP compared with FOXO1A alone [16].
• Furthermore, in HEC-1B cells, FOXO1A increased IGFBP1 promoter activity, and coexpression of PGRA or PGRB further increased the promoter activity in a cooperative manner [2].
• When FKHR and HOXA10 are expressed together, promoter activity is markedly up-regulated, which is indicative of cooperativity [18].

Analytical, diagnostic and therapeutic context of FOXO1

• In addition, immunoprecipitation of HuF nuclear proteins with a PGR antibody followed by immunoblotting with anti-FOXO1A revealed that these two proteins interact in these cells [2].
• By microarray analysis, we determined that Pax3/FKHR altered the expression of gene targets in a manner quantitatively and qualitatively distinct from Pax3 [5].
• Using pulsed-field and fluorescence in situ hybridization analyses, we demonstrate that the 130kb FKHR intron 1 is rearranged in t(2;13)-containing alveolar rhabdomyosarcomas [36].
• Fork-head box class-O 1 (FOXO1) was strongly activated, which was confirmed in vitro and in vivo by electrophoretic mobility shift assay [32].
• Both alveolar and embryonal components of the mixed ARMS/ERMS subtype were negative for PAX3, PAX7, and FKHR rearrangements, a surprising finding confirmed by RT-PCR and/or conventional karyotyping [37].

References