Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance

Çagdap Tazearslan, Srinivas Ayyadevara, Puneet Bharill, Robert J Shmookler Reis

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Insulin/IGF-1 signaling (IIS) regulates development and metabolism, and modulates aging, of Caenorhabditis elegans. In nematodes, as in mammals, IIS is understood to operate through a kinase-phosphorylation cascade that inactivates the DAF-16/FOXO transcription factor. Situated at the center of this pathway, phosphatidylinositol 3-kinase (P13K) phosphorylates PIP2 to form PIP3, a phospholipid required for membrane tethering and activation of many signaling molecules. Nonsense mutants of age-1, the nematode gene encoding the class-I catalytic subunit of PI3K, produce only a truncated protein lacking the kinase domain, and yet confer 10-fold greater longevity on second-generation (F2) homozygotes, and comparable gains in stress resistance. Their F1 parents, like weaker age-1 mutants, are far less robust-implying that maternally contributed trace amounts of PI3K activity or of PIP3 block the extreme age-1 phenotypes. We find that F2-mutant adults have >10% of wild-type kinase activity in vitro and >60% of normal phosphoprotein levels in vivo. Inactivation of PI3K not only disrupts PIP3-dependent kinase signaling, but surprisingly also attenuates transcripts of numerous IIS components, even upstream of PI3K, and those of signaling molecules that cross-talk with IIS. The age-1(mg44) nonsense mutation results, in F2 adults, in changes to kinase profiles and to expression levels of multiple transcripts that distinguish this mutant from F1 age-1 homozygotes, a weaker age-1 mutant, or wild-type adults. Most but not all of those changes are reversed by a second mutation to daf-16, implicating both DAF-16/ FOXO-dependent and -independent mechanisms. RNAi, silencing genes that are downregulated in long-lived worms, improves oxidative-stress resistance of wild-type adults. It is therefore plausible that attenuation of those genes in age-1(mg44)-F2 adults contributes to their exceptional survival. IIS in nematodes (and presumably in other species) thus involves transcriptional as well as kinase regulation in a positive-feedback circuit, favoring either survival or reproduction. Hyperlongevity of strong age-1(mg44) mutants may result from their inability to reset this molecular switch to the reproductive mode.

Original languageEnglish (US)
JournalPLoS Genetics
Volume5
Issue number4
DOIs
StatePublished - Apr 2009
Externally publishedYes

Fingerprint

stress resistance
Insulin-Like Growth Factor I
stress tolerance
nematode
phosphotransferases (kinases)
Phosphatidylinositol 3-Kinases
Phosphotransferases
Nematoda
Insulin
phosphatidylinositol 3-kinase
insulin
mutants
Homozygote
Phosphatidylinositol 3-Kinase
MHC Class I Genes
homozygosity
Nonsense Codon
Phosphoproteins
Caenorhabditis elegans
gene

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance. / Tazearslan, Çagdap; Ayyadevara, Srinivas; Bharill, Puneet; Reis, Robert J Shmookler.

In: PLoS Genetics, Vol. 5, No. 4, 04.2009.

Research output: Contribution to journalArticle

Tazearslan, Çagdap ; Ayyadevara, Srinivas ; Bharill, Puneet ; Reis, Robert J Shmookler. / Positive feedback between transcriptional and kinase suppression in nematodes with extraordinary longevity and stress resistance. In: PLoS Genetics. 2009 ; Vol. 5, No. 4.
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