daf-16;shc-1

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Genetic mutants with daf-16, shc-1 alterations

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

Temperature °C
23
Diet
NGM
Lifespan (days)
11.1
Lifespan change (compared to wild type)
-22.92%
Phenotype
Overexpression of daf-16 extended the life span of shc-1 mutant animals. However, the animals carrying integrated daf-16::gfp did not live as long as wild-type animals, suggesting that either daf-16::gfp on its own results in a phenotype or SHC-1 may have additional effects on other lifespan-promoting factors that have to be identified.
Lifespan comparisons
Double mutant daf-16(OE);shc-1(ok198) has a lifespan of 11.1 days, while single mutant daf-16(OE) has a lifespan of 15.8 days, single mutant shc-1(ok198) has a lifespan of 8.8 days and wild type has a lifespan of 14.4 days.
Type of interaction
See methods
Opposite lifespan effects of single mutants
Citation
View abstract
Neumann-Haefelin E et al., 2008, SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans. Genes Dev. 22(19):2721-35 18832074 Click here to select all mutants from this PubMed ID in the graph
Abstract
Correlative evidence links stress, accumulation of oxidative cellular damage, and aging in several species. Genetic studies in species ranging from yeast to mammals revealed several pathways regulating stress response and life span, including caloric intake, mitochondrial respiration, insulin/IGF-1 (IIS), and JNK (c-Jun N-terminal kinase) signaling. How IIS and JNK signaling cross-talk to defend against diverse stressors contributing to aging is of critical importance but, so far, only poorly understood. In this study, we demonstrate that the adaptor protein SHC-1, the Caenorhabditis elegans homolog of human p52Shc, coordinates mechanisms of stress response and aging. Using genetic and biochemical approaches, we discover that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1 function results in accelerated aging and enhanced sensitivity to heat, oxidative stress, and heavy metals, whereas expression of human p52Shc rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding to MEK-1 kinase. Both aspects converge on controlling the nuclear translocation and activation of the FOXO transcription factor DAF-16. Our findings establish C. elegans SHC-1 as a critical scaffold that directly cross-connects the two parallel JNK and IIS pathways and help to explain how these signaling cascades cooperate to ascertain normal stress response and life span in C. elegans.

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

Temperature °C
23
Diet
NGM; IPTG; HT115
Lifespan (days)
10.1
Lifespan change (compared to wild type)
-34.42%
Phenotype
Animals treated with daf-16(RNAi) indeed lived as long as shc-1 mutants, and daf-16(RNAi) did not further reduce shc-1-shortened life span.
Lifespan comparisons
Double mutant daf-16(RNAi);shc-1(ok198) has a lifespan of 10.1 days, while single mutant daf-16(RNAi) has a lifespan of 10.1 days, single mutant shc-1(ok198) has a lifespan of 10.8 days and wild type has a lifespan of 15.4 days.
Type of interaction
See methods
Dependent
Citation
View abstract
Neumann-Haefelin E et al., 2008, SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans. Genes Dev. 22(19):2721-35 18832074 Click here to select all mutants from this PubMed ID in the graph
Abstract
Correlative evidence links stress, accumulation of oxidative cellular damage, and aging in several species. Genetic studies in species ranging from yeast to mammals revealed several pathways regulating stress response and life span, including caloric intake, mitochondrial respiration, insulin/IGF-1 (IIS), and JNK (c-Jun N-terminal kinase) signaling. How IIS and JNK signaling cross-talk to defend against diverse stressors contributing to aging is of critical importance but, so far, only poorly understood. In this study, we demonstrate that the adaptor protein SHC-1, the Caenorhabditis elegans homolog of human p52Shc, coordinates mechanisms of stress response and aging. Using genetic and biochemical approaches, we discover that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1 function results in accelerated aging and enhanced sensitivity to heat, oxidative stress, and heavy metals, whereas expression of human p52Shc rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding to MEK-1 kinase. Both aspects converge on controlling the nuclear translocation and activation of the FOXO transcription factor DAF-16. Our findings establish C. elegans SHC-1 as a critical scaffold that directly cross-connects the two parallel JNK and IIS pathways and help to explain how these signaling cascades cooperate to ascertain normal stress response and life span in C. elegans.

Search genes: daf-16 shc-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

3565745
shc-1
View on GenAge (shc-1)
WBGene00018788

SHC-transforming protein homolog 1

Locus: CELE_F54A5.3

Wormbase description: shc-1 encodes four proteins by multiple splicing, three of which are rather small (52-81 residues); however, one isoform (F54A5.3A, 316 residues) is a ortholog of vertebrate Shc proteins (e.g., p52/p46SHC and p66SHC); like its orthologs, F54A5.3A has a PTB and an SH2 domain in N- to C-terminal order; shc-1 interacts with both the JNK and insulin signaling pathways to regulate stress response and adult life span; SHC-1::GFP is widely expressed during postembryonic development and localizes to both the cytoplasm and the nucleus.

Orthologs of daf-16;shc-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Mus musculus	Foxo6;Shc1
Mus musculus	Foxo6;Shc3
Mus musculus	Foxo6;Shc4
Mus musculus	Foxo6;Shc2
Mus musculus	Foxo1;Shc1
Mus musculus	Foxo1;Shc3
Mus musculus	Foxo1;Shc4
Mus musculus	Foxo1;Shc2
Mus musculus	Foxo4;Shc1
Mus musculus	Foxo4;Shc3
Mus musculus	Foxo4;Shc4
Mus musculus	Foxo4;Shc2
Mus musculus	Foxo3;Shc1
Mus musculus	Foxo3;Shc3
Mus musculus	Foxo3;Shc4
Mus musculus	Foxo3;Shc2
Mus musculus	Shc1;Foxo6
Mus musculus	Shc1;Foxo1
Mus musculus	Shc1;Foxo4
Mus musculus	Shc1;Foxo3
Mus musculus	Shc3;Foxo6
Mus musculus	Shc3;Foxo1
Mus musculus	Shc3;Foxo4
Mus musculus	Shc3;Foxo3
Mus musculus	Shc4;Foxo6
Mus musculus	Shc4;Foxo1
Mus musculus	Shc4;Foxo4
Mus musculus	Shc4;Foxo3
Mus musculus	Shc2;Foxo6
Mus musculus	Shc2;Foxo1
Mus musculus	Shc2;Foxo4
Mus musculus	Shc2;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 shc-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Shc
Mus musculus	Shc1
Mus musculus	Shc3
Mus musculus	Shc4
Mus musculus	Shc2