Characterization of Novel Regulators of FoxO Transcription Factors.

FoxO transcription factors were first implicated as regulators of longevity in C. elegans. Reducing insulin/insulin-like growth factor signaling (ILS) extends C. elegans life span in a manner dependent on DAF-16/FoxO. This life span-promoting role of FoxO is potentially conserved, as reducing ILS also enhances mammalian longevity. Additionally, evidence supports roles for FoxO in modulating age-associated diseases in humans, including cancer, osteoporosis, and metabolic dysregulation. Understanding the regulatory mechanisms controlling FoxO activity will supplement our knowledge of age-associated diseases, and possibly also shed light on the biology of aging. In C. elegans, ILS reduction causes an increase in DAF-16/FoxO activity due to its translocation to the nucleus. Nuclear DAF-16/FoxO induces transcriptional programs that promote longevity. We have discovered the EAK pathway, a novel, conserved pathway that inhibits the C. elegans FoxO transcription factor DAF-16. The EAK pathway acts in parallel to PI3K/Akt to inhibit DAF-16/FoxO, independent of controlling its subcellular localization. EAKs do so, at least in part, by promoting the activity of a conserved steroid hormone signaling pathway. This novel mechanism of DAF-16/FoxO inhibition represents a new avenue to pursue to strengthen our understanding of FoxO regulation. To illuminate the mechanism underlying EAK pathway inhibition of DAF-16/FoxO activity, we performed an unbiased genetic screen to identify suppressors of an eak;akt mutant dauer arrest phenotype (seak mutants). seak genes are predicted to encode molecules that are required to promote dauer arrest by activating DAF-16/FoxO. We have characterized two seak genes: First, we discovered that a conserved Ras GTPase activating protein regulates DAF-16/FoxO activity, likely via the EAK pathway. Second, we have identified a novel function of dosage compensation in C. elegans, discovering that dosage compensation can influence DAF-16/FoxO via the coordinated regulation of ILS pathway genes expressed on the X chromosome. This represents the first elucidation of a post-embryonic function for the dosage compensation complex and suggests that the complex itself might be under the control of signaling pathways that are responsive to the environment. Looking forward, conserved eak and seak genes represent novel therapeutic targets for the modulation of FoxO activity to aid in the fight against diseases of aging.