[Researcher Q.]: What are the downstream targets of the daf-16/FOXO transcription factor in C. elegans, and how do they influence stress resistance?

(Requires the AI to extract pathway-level details and connect them to biological outcomes.)

Researcher Mode A.: The DAF-16/FOXO transcription factor in Caenorhabditis elegans is a crucial regulator of stress resistance and longevity. It acts downstream of the insulin/IGF-1 signaling (IIS) pathway and influences various physiological processes by regulating multiple target genes.

  1. Stress Resistance and Longevity: DAF-16 regulates genes involved in stress response, metabolism, and longevity. It is activated under conditions of reduced IIS, such as dietary restriction or stress, leading to increased stress resistance and lifespan extension in C. elegans[^1^][^2^].
  2. Interaction with Other Pathways: DAF-16 interacts with other signaling pathways, such as the AMPK and JNK pathways, which further enhance its activity. AMPK, a key energy sensor, phosphorylates DAF-16, promoting its nuclear localization and activity[^1^][^3^][^4^].
  3. Transcriptional Regulation: DAF-16 can activate or repress a wide array of genes that encode for heat shock proteins, antioxidant enzymes, and other stress-responsive proteins. These genes help in mitigating oxidative stress and improving the organism’s ability to withstand environmental stressors[^1^][^2^].
  4. Synergistic Effects with SKN-1: DAF-16 works in conjunction with SKN-1, another transcription factor homologous to NRF2 in mammals, to regulate oxidative stress response genes. This synergistic action enhances the overall stress resistance of the organism[^2^][^5^].
  5. Cellular and Molecular Effects: The activation of DAF-16 leads to a cascade of molecular events, including the upregulation of genes involved in detoxification, repair, and maintenance of cellular homeostasis. This results in improved stress tolerance and contributes to the organism’s longevity[^1^][^3^].

Overall, DAF-16/FOXO plays a pivotal role in modulating stress resistance in C. elegans through its regulation of downstream genes and interaction with other signaling pathways.

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