Transcription factors of the forkhead box, class O (FoxO) family are

Transcription factors of the forkhead box, class O (FoxO) family are important regulators of the cellular stress response and promote the cellular antioxidant defense. mutants of were analyzed with respect to genetic traits contributing to their longevity. It was found that insulin-like signaling along the cascade orthologous to the mammalian insulin receptor/phosphoinositide 3-kinase/Akt (InsR/PI3K/Akt) cascade was involved in that mutants with impaired signaling along this cascade experienced extended life spans [4] (Fig. 1). It was then demonstrated that this gene conferred this life span extension [5] and that DAF-16 (DAF, dauer formation) is usually a transcription factor of the Fox family (specifically, a FoxO orthologue) essential to this process [6,7]. Open in a separate windows Fig. 1 Insulin signaling in mammalian cells and in transgenic strain TJ356 stably expresses a DAF-16::GFP fusion protein. DAF-16::GFP accumulates in nuclei upon exposure of worms to an oxidative stress (induced by diamide, a Empagliflozin cost thiol oxidizing agent). Speckles (arrow) represent nuclei with DAF-16::GFP. Mutants with deficient InsR orthologue [8], were then shown to not only display a long-lived phenotype but also a phenotype (Oxr) characterized by oxidative stress resistance: A (but neither nor mutants, which was prevented by an additional mutation [9]. These findings suggested that this expression of genes coding for antioxidant enzymes such as superoxide dismutases might be under the control of forkhead-type transcription factors. In fact, expression of the human Mn-SOD (mitochondrial SOD-2 in humans) was demonstrated to be transcriptionally controlled by the human DAF-16 orthologue, the forkhead Empagliflozin cost box transcription factor, FoxO3a [11]. Despite the fact that it was later exhibited that SOD-3 is not essential to the longevity phenotype in mutants [12], a link was established between forkhead box transcription factors and cellular antioxidant defense. The purpose of this evaluate is usually Empagliflozin cost to provide an overview on the role of FoxO transcription factors in the cellular response to (oxidative) stress C including antioxidant defense C and on the contribution of redox signaling to the biological activity of FoxOs. Four FoxO proteins are present in humans (Fig. 2), FoxO1a, FoxO3a, FoxO4 and FoxO6 (for an overview on FoxO nomenclature, see [13]). All are widely expressed in diverse tissues [14] C including FoxO6, which has frequently been said to be primarily found in brain, but has now been shown to be ubiquitously expressed as well [15]. In terms of a functional classification of FoxO target genes, three major categories are stress response and antioxidative defense, metabolism, and cell death and proliferation [16]. Open in a separate windows Fig. 2 Domain name organization of human FoxO Empagliflozin cost proteins. Positions of the most conserved domains and of some functionally characterized sequence motifs in human FoxO proteins are depicted. The figures next to the Empagliflozin cost domain name or motif indicate its beginning and end within the sequence. Total length (in aa, amino acids) of each FOXO protein is usually indicated to the right of its schematic depiction. CR1 and CR3, conserved regions 1 and 3; CR3 represents a conserved C-terminal transactivation domain name [326,327]. FH/DBD, forkhead box/DNA-binding domain name [129,309,328]; NLS, nuclear localization transmission; NES, nuclear export sequence. The amino acid sequence range of FoxO4 NLS is usually according to Obsilova et al. [329]. The corresponding homologous regions are depicted for FoxO1a, FoxO3a, and FoxO6 RGS17 NLS. Whereas NES regions were defined for FoxO1a, 3a and 4 [330C332], the presence of a NES in FoxO6 is being debated [312,313]. The plan and figures depicted are based on the following NCBI RefSeq (National Center for Biotechnology Information Reference Sequence Database; [333]) entries: FoxO1a C “type”:”entrez-protein”,”attrs”:”text”:”NP_002006.2″,”term_id”:”9257222″,”term_text”:”NP_002006.2″NP_002006.2 (GI:9257222); FoxO3a C “type”:”entrez-protein”,”attrs”:”text”:”NP_001446.1″,”term_id”:”4503739″,”term_text”:”NP_001446.1″NP_001446.1 (GI:4503739); FoxO4 C “type”:”entrez-protein”,”attrs”:”text”:”NP_005929.2″,”term_id”:”103472003″,”term_text”:”NP_005929.2″NP_005929.2 (GI:103472003); FoxO6 C “type”:”entrez-protein”,”attrs”:”text”:”NP_001278210.2″,”term_id”:”849540648″,”term_text”:”NP_001278210.2″NP_001278210.2 (GI:849540648). 2.?FoxO target genes: antioxidant defense FoxO targets.