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Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation.

Chen AT, Guo C, Dumas KJ, Ashrafi K, Hu PJ - Aging Cell (2013)

Bottom Line: Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization.Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo.Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.

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Effects of sgk-1 mutations on lifespan. (A) Schematic of the sgk-1 genomic locus (not to scale). Locations of the ft15 missense gain-of-function, ok538 deletion, and mg455 nonsense mutations are shown. Exons encoding the kinase domain are colored red. (B) Lifespans of sgk-1 mutants ft15 (gf), ok538 ( #1), and mg455 ( #2). (C) Effect of the daf-16(mu86)  mutation on the lifespans of sgk-1(gf) animals. (D) Effect of sgk-1(gf) on the lifespan of akt-1(mg306)  mutant animals. (E) Effect of sgk-1(gf) on the lifespan of hcf-1(pk924)  mutant animals. Raw data and statistics are presented in Table S1.
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fig01: Effects of sgk-1 mutations on lifespan. (A) Schematic of the sgk-1 genomic locus (not to scale). Locations of the ft15 missense gain-of-function, ok538 deletion, and mg455 nonsense mutations are shown. Exons encoding the kinase domain are colored red. (B) Lifespans of sgk-1 mutants ft15 (gf), ok538 ( #1), and mg455 ( #2). (C) Effect of the daf-16(mu86) mutation on the lifespans of sgk-1(gf) animals. (D) Effect of sgk-1(gf) on the lifespan of akt-1(mg306) mutant animals. (E) Effect of sgk-1(gf) on the lifespan of hcf-1(pk924) mutant animals. Raw data and statistics are presented in Table S1.

Mentions: We and others have shown that the sgk-1(mg455) mutation shortens lifespan (Soukas et al., 2009; Alam et al., 2010). The mg455 allele is a nonsense mutation that is predicted to result in truncation of SGK-1 within its kinase domain (Soukas et al., 2009); therefore, this is likely to be a mutation. A third group has shown that the sgk-1(ok538) deletion mutation, which is predicted to remove half of the SGK-1 kinase domain and is also probably a mutation (Hertweck et al., 2004), also reduces lifespan (Kwon et al., 2010). We confirmed these results by measuring the lifespans of both sgk-1(ok538) and sgk-1(mg455) mutants in the same assay (Fig. 1B and Table S1). sgk-1(ok538) (heretofore referred to as ‘ #1’) and sgk-1(mg455) (heretofore referred to as ‘ #2’) each shorten mean lifespan by at least 27.5% and median lifespan by at least 19.0% and 33.3%, respectively (P < 0.0001 by the log-rank test). The observation that two outcrossed strains harboring independently isolated sgk-1 mutations both have short lifespans compared with wild-type animals strongly suggests that these short lifespan phenotypes are a consequence of reduced SGK-1 activity. These results contrast with the reported lifespan extension induced by sgk-1 RNAi (Hertweck et al., 2004) and are consistent with a model whereby SGK-1 promotes longevity.


Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation.

Chen AT, Guo C, Dumas KJ, Ashrafi K, Hu PJ - Aging Cell (2013)

Effects of sgk-1 mutations on lifespan. (A) Schematic of the sgk-1 genomic locus (not to scale). Locations of the ft15 missense gain-of-function, ok538 deletion, and mg455 nonsense mutations are shown. Exons encoding the kinase domain are colored red. (B) Lifespans of sgk-1 mutants ft15 (gf), ok538 ( #1), and mg455 ( #2). (C) Effect of the daf-16(mu86)  mutation on the lifespans of sgk-1(gf) animals. (D) Effect of sgk-1(gf) on the lifespan of akt-1(mg306)  mutant animals. (E) Effect of sgk-1(gf) on the lifespan of hcf-1(pk924)  mutant animals. Raw data and statistics are presented in Table S1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824081&req=5

fig01: Effects of sgk-1 mutations on lifespan. (A) Schematic of the sgk-1 genomic locus (not to scale). Locations of the ft15 missense gain-of-function, ok538 deletion, and mg455 nonsense mutations are shown. Exons encoding the kinase domain are colored red. (B) Lifespans of sgk-1 mutants ft15 (gf), ok538 ( #1), and mg455 ( #2). (C) Effect of the daf-16(mu86) mutation on the lifespans of sgk-1(gf) animals. (D) Effect of sgk-1(gf) on the lifespan of akt-1(mg306) mutant animals. (E) Effect of sgk-1(gf) on the lifespan of hcf-1(pk924) mutant animals. Raw data and statistics are presented in Table S1.
Mentions: We and others have shown that the sgk-1(mg455) mutation shortens lifespan (Soukas et al., 2009; Alam et al., 2010). The mg455 allele is a nonsense mutation that is predicted to result in truncation of SGK-1 within its kinase domain (Soukas et al., 2009); therefore, this is likely to be a mutation. A third group has shown that the sgk-1(ok538) deletion mutation, which is predicted to remove half of the SGK-1 kinase domain and is also probably a mutation (Hertweck et al., 2004), also reduces lifespan (Kwon et al., 2010). We confirmed these results by measuring the lifespans of both sgk-1(ok538) and sgk-1(mg455) mutants in the same assay (Fig. 1B and Table S1). sgk-1(ok538) (heretofore referred to as ‘ #1’) and sgk-1(mg455) (heretofore referred to as ‘ #2’) each shorten mean lifespan by at least 27.5% and median lifespan by at least 19.0% and 33.3%, respectively (P < 0.0001 by the log-rank test). The observation that two outcrossed strains harboring independently isolated sgk-1 mutations both have short lifespans compared with wild-type animals strongly suggests that these short lifespan phenotypes are a consequence of reduced SGK-1 activity. These results contrast with the reported lifespan extension induced by sgk-1 RNAi (Hertweck et al., 2004) and are consistent with a model whereby SGK-1 promotes longevity.

Bottom Line: Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization.Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo.Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.

Show MeSH
Related in: MedlinePlus