daf-16;pdk-1

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Genetic mutants with daf-16, pdk-1 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
25
Lifespan (days)
15.0
Lifespan change (compared to wild type)
-11.76%
Lifespan comparisons
Double mutant daf-16(m27);pdk-1(sa680) has a lifespan of 15.0 days, while single mutant pdk-1(sa680) has a lifespan of 27.0 days and wild type has a lifespan of 17.0 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Paradis S et al., 1999, A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev. 13(11):1438-52 10364160 Click here to select all mutants from this PubMed ID in the graph
Abstract
An insulin receptor-like signaling pathway regulates Caenorhabditis elegans metabolism, development, and longevity. Inactivation of the insulin receptor homolog DAF-2, the AGE-1 PI3K, or the AKT-1 and AKT-2 kinases causes a developmental arrest at the dauer stage. A null mutation in the daf-16 Fork head transcription factor alleviates the requirement for signaling through this pathway. We show here that a loss-of-function mutation in pdk-1, the C. elegans homolog of the mammalian Akt/PKB kinase PDK1, results in constitutive arrest at the dauer stage and increased life span; these phenotypes are suppressed by a loss of function mutation in daf-16. An activating mutation in pdk-1 or overexpression of wild-type pdk-1 relieves the requirement for AGE-1 PI3K signaling. Therefore, pdk-1 activity is both necessary and sufficient to propagate AGE-1 PI3K signals in the DAF-2 insulin receptor-like signaling pathway. The activating mutation in pdk-1 requires akt-1 and akt-2 gene activity in order to suppress the dauer arrest phenotype of age-1. This indicates that the major function of C. elegans PDK1 is to transduce signals from AGE-1 to AKT-1 and AKT-2. The activating pdk-1 mutation is located in a conserved region of the kinase domain; the equivalent amino acid substitution in human PDK1 activates its kinase activity toward mammalian Akt/PKB.

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
20
Lifespan (days)
13.07
Lifespan change (compared to wild type)
-20.11%
Lifespan comparisons
Double mutant daf-16(mgdf50);pdk-1(RNAi) has a lifespan of 13.07 days, while single mutant daf-16(mgdf50) has a lifespan of 13.86 days and wild type has a lifespan of 16.36 days.
Type of interaction
See methods
Partially known monotony. Negative epistasis
Citation
View abstract
Chamoli M et al., 2014, A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans. Aging Cell. 13(4):641-55 24655420 Click here to select all mutants from this PubMed ID in the graph
Abstract
Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake. This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism. The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.

Search genes: daf-16 pdk-1

Entrez ID
Symbol
GenAge
Wormbase ID

172981
daf-16
View on GenAge (daf-16)
WBGene00000912

Forkhead box protein O;hypothetical protein

Locus: CELE_R13H8.1

Wormbase description: daf-16 encodes the sole C. elegans forkhead box O (FOXO) homologue; DAF-16 functions as a transcription factor that acts in the insulin/IGF-1-mediated signaling (IIS) pathway that regulates dauer formation, longevity, fat metabolism, stress response, and innate immunity; DAF-16 regulates these various processes through isoform-specific expression, isoform-specific regulation by different AKT kinases, and differential regulation of target genes; DAF-16 can interact with the CBP-1 transcription cofactor in vitro, and interacts genetically with other genes in the insulin signaling and with daf-12, which encodes a nuclear hormone receptor; DAF-16 is activated in response to DNA damage during development and co-regulated by EGL-27, alleviates DNA-damage-induced developmental arrest by inducing DAF-16-associated element (DAE)-regulated genes; DAF-16 is broadly expressed but displays isoform-specific tissue enrichment; DAF-16 localizes to both the cytoplasm and the nucleus, with the ratio between the two an important regulator of function.

Entrez ID
Symbol
GenAge
Wormbase ID

180475
pdk-1
View on GenAge (pdk-1)
WBGene00003965

3-phosphoinositide-dependent protein kinase 1

Locus: CELE_H42K12.1

Wormbase description: pdk-1 encodes the C. elegans 3-phosphoinositide-dependent kinase 1 ortholog; PDK-1 is a component of the DAF-2/insulin receptor-like signaling pathway and accordingly, functions to regulate such processes as dauer larvae formation, longevity, and salt chemotaxis learning; genetic analyses indicate that, in regulating dauer arrest, PDK-1 acts downstream of AGE-1/PI3K and upstream of the AKT-1 and AKT-2 kinases; a PDK-1::GFP fusion protein is expressed broadly beginning in late stage embryos and continuing on through adulthood; expression is seen in head, tail, and ventral cord motor neurons, pharyngeal tissues, hypodermal cells, the intestine, and the somatic gonad; in neurons, the PDK-1::GFP localizes to cell bodies and processes, with occasional expression seen in some neuronal nuclei.

Orthologs of daf-16;pdk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Pdpk1
Mus musculus	Foxo1;Pdpk1
Mus musculus	Foxo4;Pdpk1
Mus musculus	Foxo3;Pdpk1
Mus musculus	Pdpk1;Foxo6
Mus musculus	Pdpk1;Foxo1
Mus musculus	Pdpk1;Foxo4
Mus musculus	Pdpk1;Foxo3

Orthologs of daf-16 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6
Mus musculus	Foxo1
Mus musculus	Foxo4
Mus musculus	Foxo3

Orthologs of pdk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Pdk1
Mus musculus	Pdpk1