TI - dFOXO may integrate different forms of cellular stress . AB - The longevity phenotype of IGF-1R-deficient mice is associated with enhanced resistance to oxidative stress [3] . It is likely that this phenomenon is due to hyperactivation of FOXO proteins , as several studies have shown that FOXO transcription factors play a role in the oxidative-stress response in mammalian cells [16,17] as well as in C.elegans [49] . Our observation that dFOXO mutant flies are hypersensitive to oxidative stress confirms that , in addition to their role in insulin signaling , the role of FOXO proteins in protecting against cellular stress is highly conserved . The mechanism by which dFOXO confers oxidative-stress resistance is not yet known . In our microarray experiment , we identified several genes encoding cytochrome P450 enzymes as dFOXO target gene candidates ( Figure 6a ) . As it has been shown that cytochrome P450 enzymes reduce the toxic effects of paraquat in mice [67] , they might partially mediate the protective effect of dFOXO . Furthermore , it remains to be established whether the regulation of dFOXO by insulin is required for dFOXO's protective properties . It is tempting to speculate that distinct stress-induced signaling pathways activate dFOXO under conditions of cellular stress , in addition to the negative input from the insulin cascade , as several stress-induced PHOSphorylation sites are conserved between hFOXO3a and dFOXO ( A Brunet and ME Greenberg , personal communication ) . This view is supported by our observation that overexpression of a FOXO variant that cannot be inactivated by PKB elicits cell death , a phenotype not observed in larval tissues lacking insulin-signaling components [45] . This result argues that dFOXO induces cellular responses that are independent of insulin . The emerging model postulates that positive and negative inputs converge on FOXO proteins in response to different environmental conditions , making them central and important integrators controlling cellular ( cell -cycle progression ) and organismal adaptations ( dauer formation , diapause and longevity ; see Figure 7 ) . Elucidating the positive inputs that converge on FOXO , by mutating conserved PHOSphorylation sites in the single Drosophila homolog of this class , should help us to better understand dFOXO's integrator function .