Disease relevance of FOXO3

• These studies revealed that adenoviral overexpression of FKHRL1 and FKHR in the LAPC4 prostate cancer cell line resulted in apoptosis and induced the expression of many genes that affect cellular proliferation or survival [1].
• According to recent data reported by Yamamura et al., (J Biol Chem 2006; 281:5267-76), RUNX3 interacts with FoxO3a/FKHRL1 expressed in gastric cancer cells to activate Bim and induce apoptosis [2].
• In contrast, nuclear Cdc25A overexpression caused dephosphorylation and nuclear retention of the proapoptotic transcription factor Forkhead in rhabdomyosarcoma-like 1 (FKHRL1) in human N.1 ovarian carcinoma cells [3].
• Here, we show that ionizing radiation can promote FOXO3a (FKHRL1) transcriptional activity and protein expression level, and induce nuclear translocation of FOXO3a in Saos2, a p53-null osteosarcoma cell line [4].
• 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 [5].

High impact information on FOXO3

• Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene [6].
• Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation [6].
• Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of CD4(+) T(CM) depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a) [7].
• Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro [8].
• Efficient nuclear export of FKHRL1 requires both intrinsic NES sequences within FKHRL1 and phosphorylation/14-3-3 binding [9].

Chemical compound and disease context of FOXO3

• Our findings suggest that cisplatin causes the phosphorylation of FKHRL1 via a phosphatidylinositol 3-kinase/Akt cascade, and inhibition of this cascade sensitizes ovarian cancer cells to cisplatin [10].
• Induction of apoptosis by L-NMMA, via FKHRL1/ROCK pathway in human gastric cancer cells [11].

Biological context of FOXO3

• We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1 [12].
• The present work demonstrates that MUC1 regulates FKHRL1/FOXO3a, a member of the forkhead family of transcription factors that induces oxidant scavenging and DNA repair [13].
• These studies show IGF-I phosphorylation of FKHR and FKHRL1 via a PI3-K-dependent pathway in NBL cells [14].
• Additional experiments showed that selenium increased the transactivation activity of FOXO3A, as evidenced by a reporter gene assay, as well as by the elevated expression of Bim (a target gene of FOXO3A) [15].
• A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction [16].

Anatomical context of FOXO3

• In conjunction with the evidence that FKHRL1 is expressed in normal human erythroid progenitor cells and erythroblasts, the results suggest that FKHRL1 plays an important role in erythropoiesis as one of the downstream target molecules of PI3K-Akt [16].
• Here, we show that FOXO3a (also known as FKHRL1) is a new substrate of caspase-3-like proteases during apoptosis in T lymphocytes [17].
• In MDA-468/PTEN but not in vector controls, treatment with ZD1839 inhibited P-Akt levels, induced relocalization of the Forkhead factor FKHRL1 to the cell nucleus, and increased FKHRL1-dependent transcriptional activity [18].
• NGF rapidly induced the phosphorylation of FKHRL1 in PC12 cells [19].
• Further characterization of FKHRL1 and its related family members should shed light on the transcriptional mechanisms of this fork head gene subfamily and their role in T helper cell differentiation and regulation of cell growth [20].

Associations of FOXO3 with chemical compounds

• PI3-K inhibitor, LY294002, reduced IGF-I-stimulated phosphorylation of FKHR, FKHRL1, and Akt, but did not affect Erk phosphorylation [14].
• Increased Akt phosphorylation following treatment with doxorubicin was accompanied by increased phosphorylation of glycogen synthase kinase 3beta (GSK3beta) and FOXO3A, which are substrates of Akt (both GSK3beta and FOXO3A lose their proapoptotic activities when they are phosphorylated) [15].
• EPO induced phosphorylation of a member of the trancription factor Forkhead family, FKHRL1, at threonine 32 and serine 253 in a dose- and time-dependent manner in UT-7/EPO cells [16].
• To demonstrate this hypothesis, we generated a tamoxifen-inducible "active FKHRL1" FKHRL1-TM (a triple mutant of FKHRL1, in which all three Akt phosphorylation sites have been mutated), estrogen receptor system in the KCL22 cell line [21].
• The addition of tamoxifen inhibited the cell growth indicating that overexpression of FKHRL1 in the nucleus antagonized deregulated proliferation of CML cells [21].

Enzymatic interactions of FOXO3

• Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a) [12].
• We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites [22].

Regulatory relationships of FOXO3

• Forkhead factor FKHRL1 binds in vitro to the three consensus sequences and can activate TGF-beta2 promoter in normal and Akt-transformed cell lines [23].
• A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells [21].
• RESULTS: We demonstrate that Hcy induces dephosphorylation of Akt and FKHRL1 and upregulates the cyclin-dependent kinase inhibitors p27(kip1) in a time- and dose-dependent manner [24].
• In addition, Epo treatment of erythroid progenitors induces phosphorylation of a member of the Forkhead family (FH) of transcription factors FKHRL1, downstream of activation of the Akt kinase [25].
• Similarly, induction of FasL by the Akt-regulated forkhead transcription factor FKHRL1 was dependent upon caspase and c-Jun activation [26].

Other interactions of FOXO3

• These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites [12].
• To provide insight into the role of PTEN mutations in prostate cancer, we used microarrays to identify genes regulated by FKHRL1 and FKHR in LAPC4 prostate carcinoma cells [1].
• The three genes (HGMW-approved symbols FKHRP1, FKHRL1, and FKHRL1P1) map to chromosomal regions 5q35.2-q35.3, 6q21, and 17p11, respectively [27].
• AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily [28].
• The related family members, FKHRL1 and AFX, also bound to ER alpha in the presence of beta-estradiol [29].
• RNAi knockdown of Noxa or Bim decreased apoptosis, indicating that Noxa and Bim cooperate to mediate FKHRL1-induced cell death [30].

Analytical, diagnostic and therapeutic context of FOXO3

• Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family [20].
• CONCLUSIONS: Balloon angioplasty leads to the phosphorylation of FKHRL1 and decreased expression of p27, thereby promoting a proliferative phenotype in VSMCs in vitro and in vivo [31].
• This study reveals the importance of FKHRL1 in proliferation and viability of VSMCs and suggests that it may serve as a molecular target for interventions to reduce neointima formation after angioplasty [31].
• Moreover, exogenous expression of TM of FKHRL1 in Caov-3 cells decreased the cell viability after treatment with cisplatin [10].
• Western blot analysis revealed that Cl-F-araA induced a dose- and time-dependent downregulation of Bcl-X(L) and Mcl-1 proteins, and a dose- and time-dependent dephosphorylation of Akt and its downstream effectors (Bad, FKHRL1), particularly in vivo [32].

References