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DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans


Cancer is an age-related disease, and inhibiting insulin/insulin-like growth factor 1 (IGF-1) signaling extends lifespan and increases tumor resistance in C. elegans and mammals. To investigate how the insulin/IGF-1 pathway couples these two processes, we analyzed putative transcriptional targets of the C. elegans FOXO transcription factor DAF-16, which promotes both longevity and tumor resistance. Twenty-nine of 734 genes tested influenced germline-tumor cell proliferation or p53-dependent apoptosis. About half of these genes also affected normal aging, thereby linking these two processes mechanistically. Many of these 29 genes are orthologs of known human tumor suppressors or oncogenes, suggesting that others may be as well. Our findings implicate nuclear-pore modification in p53-dependent cell death, because inhibiting nuclear-pore genes that are upregulated by DAF-16 blocks p53-dependent cell death in the tumor, but not normal, p53-independent, germline cell death.

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Figure 1: DAF-16/FOXO target genes that inhibit the growth of gld-1 tumors.
Figure 2: DAF-16/FOXO target genes that stimulate the growth of gld-1 tumors.
Figure 3: Inhibiting nuclear pore proteins specifically prevents the germline apoptosis triggered by daf-2 mutation or genotoxic stress.
Figure 4: DCT-11 antagonizes the DNA-damage cell death pathway to inhibit germ cell death in gld-1(–) mutants.


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We thank S. Henis-Korenblit, M. Hansen and N. Gosse for careful reading of the text, and the Caenorhabditis Genetics Center and the C. elegans Gene Knockout Consortium for providing strains. This work was supported by US National Institutes of Health funding to C.K. J.P.-G. was supported by University of California San Francisco's Chancellor's fellowship. C.K. is an American Cancer Society Research Professor and a founder and director of Elixir Pharmaceuticals.

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J.P.-G. carried out all the experiments. C.K. helped to design the experiments and write the paper.

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Correspondence to Cynthia Kenyon.

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The authors declare no competing financial interests.

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Pinkston-Gosse, J., Kenyon, C. DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans. Nat Genet 39, 1403–1409 (2007).

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