daf-2;smk-1

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Genetic mutants with daf-2, smk-1 alterations

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

Temperature °C
20
Lifespan (days)
26.6
Lifespan change (compared to wild type)
45.36%
Phenotype
Reduced levels of smk-1 completely suppressed the extended longevity of daf-2(e1370) mutant animals
Lifespan comparisons
Double mutant daf-2(e1370);smk-1(RNAi) has a lifespan of 26.6 days, while single mutant daf-2(e1370) has a lifespan of 48.2 days and wild type has a lifespan of 18.3 days.
Type of interaction
See methods
Contains dependence
Citation
View abstract
Wolff S et al., 2006, SMK-1, an essential regulator of DAF-16-mediated longevity. Cell. 124(5):1039-53 16530049 Click here to select all mutants from this PubMed ID in the graph
Abstract
Insulin/IGF-1 signaling (IIS) regulates aging in worms, flies, and mice through a well-characterized, highly conserved core set of components. IIS also regulates early developmental decisions, the reproductive status of the animal, innate immunity, and stress-resistance functions. In C. elegans, the sole insulin/IGF-1 receptor, DAF-2, negatively regulates the FOXO transcription factor, DAF-16. We report here on a new component of the IIS longevity pathway, SMK-1, which specifically influences DAF-16-dependent regulation of the aging process in C. elegans by regulating the transcriptional specificity of DAF-16 activity. Localization analysis of DAF-16 places SMK-1 downstream of DAF-16's phosphorylation-dependent relocation to the nucleus. Physiological and transcription analyses indicate that smk-1 is required for the innate immune, UV, and oxidative stress but not the thermal stress functions of DAF-16. SMK-1 therefore plays a role in longevity by modulating DAF-16 transcriptional specificity without affecting other processes regulated by IIS.

Temperature °C
25
Lifespan (days)
21.3
Lifespan change (compared to wild type)
44.90%
Phenotype
Forty-one gene inactivations functioned specifically within the daf-2 pathway to shorten life span, not decreasing the life span of daf-2;daf-16 animals
Lifespan comparisons
Double mutant daf-2(e1370);smk-1(RNAi) has a lifespan of 21.3 days, while single mutant daf-2(e1370) has a lifespan of 36.7 days, single mutant smk-1(RNAi) has a lifespan of 11.6 days and wild type has a lifespan of 14.7 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Samuelson AV et al., 2007, Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev. 21(22):2976-94 18006689 Click here to select all mutants from this PubMed ID in the graph
Abstract
Genetic and RNA interference (RNAi) screens for life span regulatory genes have revealed that the daf-2 insulin-like signaling pathway plays a major role in Caenorhabditis elegans longevity. This pathway converges on the DAF-16 transcription factor and may regulate life span by controlling the expression of a large number of genes, including free-radical detoxifying genes, stress resistance genes, and pathogen resistance genes. We conducted a genome-wide RNAi screen to identify genes necessary for the extended life span of daf-2 mutants and identified approximately 200 gene inactivations that shorten daf-2 life span. Some of these gene inactivations dramatically shorten daf-2 mutant life span but less dramatically shorten daf-2; daf-16 mutant or wild-type life span. Molecular and behavioral markers for normal aging and for extended life span in low insulin/IGF1 (insulin-like growth factor 1) signaling were assayed to distinguish accelerated aging from general sickness and to examine age-related phenotypes. Detailed demographic analysis, molecular markers of aging, and insulin signaling mutant test strains were used to filter progeric gene inactivations for specific acceleration of aging. Highly represented in the genes that mediate life span extension in the daf-2 mutant are components of endocytotic trafficking of membrane proteins to lysosomes. These gene inactivations disrupt the increased expression of the DAF-16 downstream gene superoxide dismutase sod-3 in a daf-2 mutant, suggesting trafficking between the insulin-like receptor and DAF-16. The activities of these genes may normally decline during aging.

Search genes: daf-2 smk-1

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

179243
smk-1
View on GenAge (smk-1)
WBGene00018285

SMEK (Dictyostelium Suppressor of MEK null) homolog

Locus: CELE_F41E6.4

Wormbase description: smk-1 encodes a novel, evolutionarily conserved protein that is orthologous to the mammalian and Dictyostelium discoideum SMEK (suppressor of MEK null) proteins; smk-1 activity is essential for several aspects of DAF-16-mediated longevity namely, the defense response to pathogenic bacteria and increased resistance to oxidative and UV-induced damage; in regulating DAF-16 activity, SMK-1 appears to act by affecting the transcription of DAF-16 target genes, such as sod-3, ctl-1, and lys-8; SMK-1 is present in the nucleus of intestinal cells, many head and tail neurons, and some hypodermal cells throughout development.

Orthologs of daf-2;smk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	flfl;InR
Mus musculus	4932429P05Rik;Insr
Mus musculus	4930415L06Rik;Insr
Mus musculus	Insr;Ppp4r3a
Mus musculus	Insr;Ppp4r3b
Mus musculus	4932429P05Rik;Igf1r
Mus musculus	4930415L06Rik;Igf1r
Mus musculus	Igf1r;Ppp4r3a
Mus musculus	Igf1r;Ppp4r3b
Mus musculus	4932429P05Rik;Insrr
Mus musculus	4930415L06Rik;Insrr
Mus musculus	Insrr;Ppp4r3a
Mus musculus	Insrr;Ppp4r3b
Mus musculus	Insr;4932429P05Rik
Mus musculus	Insr;4930415L06Rik
Mus musculus	Insr;Ppp4r3a
Mus musculus	Insr;Ppp4r3b
Mus musculus	Igf1r;4932429P05Rik
Mus musculus	Igf1r;4930415L06Rik
Mus musculus	Igf1r;Ppp4r3a
Mus musculus	Igf1r;Ppp4r3b
Mus musculus	Insrr;4932429P05Rik
Mus musculus	Insrr;4930415L06Rik
Mus musculus	Insrr;Ppp4r3a
Mus musculus	Insrr;Ppp4r3b

Orthologs of daf-2 in SynergyAge

Show in SynergyAge
Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of smk-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	flfl
Mus musculus	4932429P05Rik
Mus musculus	4930415L06Rik
Mus musculus	Ppp4r3a
Mus musculus	Ppp4r3b