FOXO proteins are the O class of the Forkhead family of proteins. Forkhead protein (FOX) was first discovered in Drosophila and when mutated results in a head structure that resembles a fork (Wiegel et al 1989). Over 100 FOX proteins have been identified since and classified as FOXA to FOXR depending on sequence similarities. The FOX family of proteins function as transcription factors and their defining feature is a DNA binding domain known as the fork head domain (Lai et al 1993). This domain is a hundred amino acids long and is highly conserved. It consists of three alpha helices and two large loop regions. The resulting structure resembles butterfly wings and the FOX proteins are sometime refer to as winged helix proteins(Clark et al 1993).
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FOXO proteins are conserved from Caenorhabidis elegans to mammals. Invertebrates have just one FOXO protein. It is known as DAF-16 in C. elegans and dFOXO in Drosophila melanogaster (Burgering et al 2002). Mammals have four FOXO proteins- FOXO1, FOXO3, FOXO4 and FOXO6 (Anderson et al 1998, Jacobs et al 2003). The mammalian FOXO proteins share the same DNA binding domain and have overlapping transcriptional targets. Nonetheless, they also have certain distinct biological functions. In mice, the lack of FOXO1 is embryonic lethal and mice that are null for FOXO1 do not survive past day 10.5(Furuyama et al 2004). FOXO3 null mice do survive but display lymphoproliferation, organ inflammation and for females, age dependent infertility(Castrillon 2003). Mice null for FOXO4, on the other hand, show no detectable adverse phenotypes(Hosaka et al 2004) Low levels of all FOXO proteins are expressed in almost all Mammalian tissues. However, each of the FOXO proteins have particular high expression in certain tissues. FOXO1 expression is highest in adipose tissue, uterus and ovaries. FOXO3 is expressed at particularly high levels in the brain, spleen and the heart. FOXO4 expression is high in both the cardiac and skeletal muscles. FOXO6 is expressed almost exclusive in the brain (Hookman et
FOXO proteins are conserved from Caenorhabidis elegans to mammals. Invertebrates have just one FOXO protein. It is known as DAF-16 in C. elegans and dFOXO in Drosophila melanogaster (Burgering et al 2002). Mammals have four FOXO proteins- FOXO1, FOXO3, FOXO4 and FOXO6 (Anderson et al 1998, Jacobs et al 2003). The mammalian FOXO proteins share the same DNA binding domain and have overlapping transcriptional targets. Nonetheless, they also have certain distinct biological functions. In mice, the lack of FOXO1 is embryonic lethal and mice that are null for FOXO1 do not survive past day 10.5(Furuyama et al 2004). FOXO3 null mice do survive but display lymphoproliferation, organ inflammation and for females, age dependent infertility(Castrillon 2003). Mice null for FOXO4, on the other hand, show no detectable adverse phenotypes(Hosaka et al 2004) Low levels of all FOXO proteins are expressed in almost all Mammalian tissues. However, each of the FOXO proteins have particular high expression in certain tissues. FOXO1 expression is highest in adipose tissue, uterus and ovaries. FOXO3 is expressed at particularly high levels in the brain, spleen and the heart. FOXO4 expression is high in both the cardiac and skeletal muscles. FOXO6 is expressed almost exclusive in the brain (Hookman et