The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

• Main Author: Michel Schmitt-Ney
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Cells
• Subjects: foxo; transcription; gene family; pi3k; akt; insulin pathway; tumor suppressor; cancer; aging; gene duplication; genetic redundancy; evolution; fox; forkhead; metabolism
• Online Access: https://www.mdpi.com/2073-4409/9/3/787

The nematode <i>Caenorhabditis elegans</i> possesses a unique (with various isoforms) FOXO transcription factor DAF-16, which is notorious for its role in aging and its regulation by the insulin-PI3K-AKT pathway. In humans, five genes (including a protein-coding pseudogene) encode for FOXO transcription factors that are targeted by the PI3K-AKT axis, such as in <i>C. elegans</i>. This common regulation and highly conserved DNA-binding domain are the pillars of this family. In this review, I will discuss the possible meaning of possessing a group of very similar proteins and how it can generate additional functionality to more complex organisms. I frame this discussion in relation to the much larger super family of Forkhead proteins to which they belong. FOXO members are very often co-expressed in the same cell type. The overlap of function and expression creates a certain redundancy that might be a safeguard against the accidental loss of FOXO function, which could otherwise lead to disease, particularly, cancer. This is one of the points that will be examined in this &#8220;family affair&#8221; report.