期刊
NATURE
卷 466, 期 7305, 页码 498-502出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature09184
关键词
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资金
- National Institutes of Health National Center for Research Resources
- National Institute of Aging [AG025891, AG031237]
- Glenn Foundation for Medical Research
- Ellison Medical Foundation
- William Randolph Hearst Foundation
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity(1-5). In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway(2,3,6,7). One of two isoforms(4,5,8), DAF-16a, is known to regulate longevity, stress response and dauer diapause(8-11). However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions(6,12), and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
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