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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.11.019 Byline: Nicole Liachko, Rachel Davidowitz, Siu Sylvia Lee Keywords: DAF-2; DAF-16; FOXO; HLH-13; Ptf1a; Dauer; Development; Caenorhabditis elegans; Insulin signaling Abstract: Insulin/IGF-signaling (IIS) affects longevity, stress resistance and metabolism in worms, flies, and mammals. The Forkhead transcription factor DAF-16/FOXO is the major downstream effector of IIS and is responsible for the activation and repression of genes that mediate the diverse effects of IIS. We surveyed a set of informatically predicted conserved DAF-16/FOXO target genes and identified the novel DAF-16 direct target hlh-13. hlh-13 is the predicted homolog of the mammalian transcription factor Ptf1a, a critical determinant of pancreatic development. We found that an hlh-13 mutant exits L1 arrest and IIS-dependent dauer diapause faster than control worms, but is not involved in lifespan or resistance to a variety of stresses. Our results have identified a novel DAF-16 target gene and linked its function to known outputs of IIS. Considering the high conservation of IIS in diverse species, our results also hint at an intriguing connection of IIS and Ptf1a in mammals. Author Affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA Article History: Received 10 June 2008; Revised 14 October 2008; Accepted 25 November 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.10.013 Byline: Ji Li (a), Muneesh Tewari (b)(c), Marc Vidal (b), Siu Sylvia Lee (a) Keywords: 14-3-3; ftt-2; par-5; daf-16; FOXO; daf-2; Insulin signaling Abstract: The Caenorhabditis elegans daf-2/insulin-like signaling pathway is critical for regulating development, longevity, metabolism and stress resistance. We identified the 14-3-3 protein FTT-2 to be a new regulatory component of this pathway. We found that RNAi knock down of ftt-2 specifically enhanced the daf-2-mediated dauer formation phenotype. Furthermore, ftt-2 knock down caused the nuclear accumulation of DAF-16/FOXO, the forkhead transcription factor that is the major downstream effecter of daf-2/insulin-like signaling, and enhanced the transcriptional activities of DAF-16. In contrast to ftt-2, RNAi knock down of par-5/ftt-1, the only other gene predicted to encode a 14-3-3 protein in C. elegans, did not show any notable effect on dauer formation, DAF-16 localization, or DAF-16 downstream gene transcription, underscoring the functional specification of FTT-2 and PAR-5 despite their high sequence homology. Using co-immunoprecipitation, we revealed that FTT-2 formed a complex with GFP-fused DAF-16 in C. elegans. Our results indicate that FTT-2 binds to DAF-16 in C. elegans and regulates DAF-16 by sequestering it in the cytoplasm. A similar mechanism of regulation of FOXO by 14-3-3I[paragraph] has been reported in mammalian cells, highlighting the high degree of conservation of the daf-2/insulin-like signaling pathway. Author Affiliation: (a) Department of Molecular Biology, Cornell University, Ithaca, NY 14850, USA (b) Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA (c) Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA 98109, USA Article History: Received 28 March 2006; Revised 9 October 2006; Accepted 10 October 2006

Two studies reveal that early-life malfunction in organelles called mitochondria brings about lasting changes in how DNA is packaged. These alterations have consequences for cellular stress responses and organismal longevity., Author(s): Siu Sylvia Lee [sup.1] , Jessica K. Tyler [sup.2] Author Affiliations: (1) Siu Sylvia Lee is in the Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York [...]

A decline in mitochondrial electron transport chain ( ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP-1/p53 and CEH-23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK-2/ AMP kinase ( AMPK) signaling. Further functional analyses suggested that CEP-1/p53 and CEH-23 act downstream of AAK-2/ AMPK signaling and CRTC-1 transcriptional coactivator to promote stress resistance and lifespan. As AAK-2, CEP-1, and CEH-23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human. [ABSTRACT FROM AUTHOR]