FOXO3A (Forkhead Box O3A, Forkhead in Rhabdomyosarcoma-like 1, AF6q21 Protein, DKFZp781A0677, FKHR2, FKHRL1, FKHRL1P2, MGC12739, MGC31925)

The superfamily of Forkhead transcription factors (FOX) consists of more than 100 members, with orthologues expressed in a variety of species ranging from yeast to man. They are characterized by a common Forkhead (or Winged Helix) domain, a variant of the helix-turn-helix motif. Forkhead family members have been shown to play key regulatory roles in embryonic development, differentiation, apoptosis, and tumorigenesis. Three Forkhead family members, termed FKHR (FOXO1a), FKHRL1 (FOXO3a), and AFX (FOXO4) were first identified at chromosomal breakpoints in human tumors, and consequently linked to tumorigenesis. It is now well established that these proteins are targets of the PI3K/PKB pathway. PI3K/PKB (Phosphatydil Inositol 3-kinase/Protein Kinase B or Akt) plays a role in oncogenic transformation. PKB/Akt substrates include components of the cell death machinery, such as BAD and caspase 9.1,9,10 Stimulation of this cascade by Nerve Growth Factor or IGF-1 leads to phosphorylation of these proteins and suppression of their proapoptotic function, partially explaining the survival effect of PKB. The identification of the transcription factor DAF16 as a PKB target in the nematode C.elegans was critical in the understanding of its link with FKHR, FKHRL1, and AFX.13 DAF16 belongs to the Forkhead family and transduces insulin-like signals. FKHR, FKHRL1, and AFX (FOXO4)1,5 are similar in sequence to DAF16 and represent the mammalian counterparts. Similarly, these proteins are PKB/AKT targets. Growth factors regulate the activity of FKHRL1, FKHR, and AFX via the PKB/PI3K pathway, by direct phosphorylation of the transcription factors. These transcription factors are inhibited by phosphorylation by PKB, the most likely mechanism being regulation of nuclear localization. In FKHRL1 (FOX3a), there are three PKB phosphorylation consensus sites, Thr32, Ser253, and Ser315. Thr32 and Ser253 are phosphorylated by PKB after induction by survival factors such as IGF-1. This results in FKHRL1 retention in the cytoplasm, and/or nuclear exclusion, and consequent inhibition of FKHRL1-dependent transcription. Survival factor withdrawal induces FKHRL1 dephosphorylation and translocation to the nucleus. Within the nucleus, the dephosphorylated FKHRL1 induces target genes such as Fas ligand, and triggers apoptosis. Growth factors suppress the transcription of death genes by triggering PKB/AKT dependent phosphorylation and inactivation of FKHRL1, and thereby promote cell survival. A similar mechanism is proposed for FKHR and AFX. It has been shown that FKHRL1/FOXO3a modulates the expression of several genes that regulate DNA repair in response to stress at the G2-M checkpoint, oxidative stress resistance, and aging. Other genes that are regulated by FKHRL1 include mitotic genes such as cyclin B and polo-like kinase (plk). Antibodies reacting specifically with FKHRL1 (FOXO3) may be useful in studying the expression and function of the protein, as well as for correlating their expression pattern with physiological functions or pathological conditions.\n\nCellular Localization: Nuclear\n\nApplications: \nSuitable for use in Immunofluorescence and Western Blot. Other applications not tested.\n\nRecommended Dilution:\nOptimal dilutions to be determined by the researcher.\n\nStorage and Stability:\nMay be stored at 4 degrees C for short-term only. For long-term storage and to avoid repeated freezing and thawing, aliquot and store at -20 degrees C. Aliquots are stable for at least 12 months at -20 degrees C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap. Further dilutions can be made in assay buffer.

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SPECIFICATIONS

Catalog Number

F9049-31A

Size

50ul

Applications

IF, WB

Hosts

Rabbit

Reactivities

Hum, Mouse, Rat

Form

0.01M PBS [pH 7.4] with 1% BSA

P Type

Pab

Purity

Purified by immunoaffinity chromatography.

Isotype

IgG

References

Kops GJ & Burgering BM Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med 77:656-65 (1999). <PUBMED:10569203>Mansouri A The role of Pax3 and Pax7 in development and cancer. Crit Rev Oncog 9:141-9 (1998). <PUBMED:9973247>Anderson MJ et al. Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 47:187-99 (1998). <PUBMED:9479491>Brennan RG The winged-helix DNA-binding motif: another helix-turn-helix takeoff. Cell 74:773-6 (1993). <PUBMED:8374950>

Additional Info

Species Crossreactivity: Crossreacts with Human and Mouse. Expected to crossreact with Rat (100% identity with immunogen) due to sequence homology.

Alternative Names

Forkhead (Drosophila) Homolog (rhabdomyosarcoma)-like 1, Forkhead Drosophila homolog of in rhabdomyosarcoma like 1, FOXO2