Disease relevance of Foxo3a

• Here we show that such inflammation requires the forkhead transcription factor Foxo3a: Foxo3a-deficient mice are resistant to two models of neutrophilic inflammation, immune complex-mediated inflammatory arthritis and thioglycollate-induced peritonitis [1].
• Foxo3a-null females showed age-dependent infertility and had abnormal ovarian follicular development [2].
• We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice [3].
• However, the cell lines derived from SCID mice that are defective in the catalytic subunit of DNA-dependent protein kinase retain elevated levels of p27 and Foxo3a proteins despite reactivation of v-Abl [4].
• We demonstrate here that MLL-FKHRL1 enhances the self-renewal of murine myeloid progenitors in vitro and induces acute myeloid leukemias in syngeneic mice [5].

High impact information on Foxo3a

• Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers [6].
• Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis [1].
• Thus, Foxo3a ensures neutrophil survival during inflammation, identifying Foxo3a as therapeutic target in inflammation [1].
• We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis [7].
• Foxo3a inhibits NF-kappaB activation, whose overactivity was responsible for T cell hyperactivity in Foxo3a-deficient mice [7].

Biological context of Foxo3a

• Here, we show that Foxo3a-/- female mice exhibit a distinctive ovarian phenotype of global follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility [8].
• As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27(kip1) [3].
• As a result, phosphorylation of Akt and its downstream targets, including FKHRL1 and GSK3alpha/beta, were reduced accordingly [9].
• Thus, it comes as a surprise in this issue of Immunity that lymphoproliferative disease in Foxo3a-deficient mice may be due to T cell hyperactivity instead of cell death defects [10].
• Apoptosis protection conferred by CD152 correlated with the up-regulation of Bcl-2 and was mediated by phosphatidylinositol 3 kinase, which prevented FasL expression through the inhibitory phosphorylation of Forkhead transcription factor FKHRL1 [11].

Anatomical context of Foxo3a

• Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-kappaB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities [7].
• Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a [8].
• Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development [12].
• 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 [13].
• Interestingly, FKHRL1 co-immunoprecipitated with Akt in PC12 cells, indicating that these two proteins can associate in these cells [14].

Associations of Foxo3a with chemical compounds

• Exposure to 20 mM glucose resulted in decreased Akt phosphorylation and enhanced nuclear translocation of forkhead box O3a (FOXO3a) [15].
• The environmental stress stimuli that induce Sgk, but not dexamethasone, strongly inhibited the nuclear transcriptional activity and increased the cytoplasmic retention of FKHRL1 [16].
• TGF beta-induced FKHRL1 phosphorylation and nuclear exclusion were inhibited by LY294002, an inhibitor of phosphatidylinositol-3 kinase [17].

Enzymatic interactions of Foxo3a

• Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a [18].
• Sgk is known to phosphorylate and negatively regulate pro-apoptotic forkhead transcription factor FKHRL1 [16].

Regulatory relationships of Foxo3a

• Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK [19].
• The role of oocyte's Akt may be to enhance follicle development and the role of oocyte's FKHRL1 may be to inhibit follicle development [12].
• By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF [12].
• Furthermore, Foxo3a is degraded through the 26S proteasome pathway in untreated cells and is induced by VCD via both Nrf2-dependent transcription and protein stabilization [20].
• Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells [14].
• Transcriptional control of Epo/Foxo3a-induced Cited2 was studied and compared with that of the Epo-repressed Foxo3a target Btg1 [21].

Other interactions of Foxo3a

• 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 [2].
• Restored Foxo3a activity reversed Flt3-ITD-mediated growth properties and dominant-negative Akt prevented Flt3-ITD-mediated cytokine independence [18].
• Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a [7].
• The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses [22].
• In turn, v-Abl reactivation reduces p27 and Foxo3a levels, thus permitting G1-arrested cells to reenter the cell cycle [4].

References