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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

Signaling from the DAF-2/insulin receptor to the DAF-16/FOXO transcription factor controls longevity, metabolism, and development in disparate phyla. To identify genes that mediate the conserved biological outputs of daf-2/insulin-like signaling, we used comparative genomics to identify 17 orthologous genes from Caenorhabditis and Drosophila, each of which bears a DAF-16 binding site in the promoter region. One-third of these DAF-16 downstream candidate genes were regulated by daf-2/insulin-like signaling in C. elegans, and RNA interference inactivation of the candidates showed that many of these genes mediate distinct aspects of daf-16 function, including longevity, metabolism, and development., The C. elegans daf-2 pathway controls longevity, metabolism, and development and is orthologous to the mammalian insulin and insulin-like growth factor 1 signaling cascade (1). Decreased daf-2 signaling causes up [...]

The 9ORF1 gene encodes an adenovirus E4 region oncoprotein that requires a C-terminal region for transforming activity. Screening a [Lambda]gt11 cDNA expression library with a 9ORF1 protein probe yielded a novel cellular PDZ domain-containing protein, 9BP-1, which binds to wild-type, but not a transformation-defective, C-terminal, mutant 9ORF1 protein. The fact that PDZ domains complex with specific sequences at the free C-terminal end of some proteins led to the recognition that the 9ORF1 C-terminal region contained such a consensus-binding motif. This discovery prompted investigations into whether the 9ORF1 protein associates with additional cellular proteins having PDZ domains. It was found that the 9ORF1 protein interacts directly, in vitro and in vivo, with the PDZ domain-containing protein hDlg/SAP97 (DLG), which is a mammalian homolog of the Drosophila discs large tumor suppressor protein and which also binds the adenomatous polyposis coli tumor suppressor protein. Of interest, in forming complexes, the 9ORF1 protein preferentially associated with the second PDZ domain of DLG, similar to adenomatous polyposis coli protein. Human T cell leukemia virus type 1 Tax and most oncogenic human papillomavirus E6 oncoproteins also possessed PDZ domain-binding motifs at their C termini and, significantly, human T cell leukemia virus type 1 Tax and human papillomavirus 18 E6 proteins bound DLG in vitro. Considering the requirement of the 9ORF1 C-terminal region in transformation, these findings suggest that interactions with the cellular factor DLG may contribute to the tumorigenic potentials of several different human virus oncoproteins.

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 [...]

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 (corresponding author); Gary Ruvkun More than sixty years ago a report appeared demonstrating that rats fed a diet containing 30-50% fewer calories live for four years [...]