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

Pinkston-Gosse, Julie; Kenyon, Cynthia

doi:10.1038/ng.2007.1

Cited by 148 publications

(104 citation statements)

References 28 publications

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“…Surprisingly, damage-induced apoptosis was strongly suppressed in the germline of daf-2(lf) mutants when compared with wild-type ( Figure 1b). Because this contradicted the weak anti-apoptotic role previously reported for daf-2 in the worm germline, 12,13 we examined two additional alleles of daf-2 ( Figure 1b) and ablated daf-2 by RNA interference (RNAi) (see below). Even though the e1370, e1391 and m596 alleles affect distinct regions of the daf-2 locus, 14 all three mutations caused strong resistance to apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Perrin

Gunda

et al. 2012

Cell Death Differ

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The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositidedependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.

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Section: Resultsmentioning

confidence: 99%

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Perrin

Gunda

et al. 2012

Cell Death Differ

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“…In addition, due to their size, some ZnONPs may reach the nucleus and interact with DNA molecules (Sharma et al, 2012a,b;Martinez et al, 2003). Several genes are biomarkers of the DNA damage and apoptosis, such as p53 (Derry et al, 2001) and BNIP3 (Yasuda et al, 1998;Pinkston-Gosse Kenyon, 2007), the orthologs of C. elegans cep-1 and dct-1, respectively. The observed increase in transcript levels of cep-1 (in wild-type and the triple mutant) and dct-1 (in wild-type only) following a ZnONP challenge suggests that exposure and apoptosis are interlinked, and supports the notion that zinc oxide nanoparticles can induce apoptosis in human cancer cells through reactive oxygen species 57…”

Section: Resultsmentioning

confidence: 99%

Metalloproteins and phytochelatin synthase may confer protection against zinc oxide nanoparticle induced toxicity in Caenorhabditis elegans

Polak

Read

Jurkschat

et al. 2014

Comparative Biochemistry and Physiology Part C: Toxicology &

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Spurgeon, David J.; Sturzenbaum, Stephen R.. 2014. Metalloproteins and phytochelatin synthase may confer protection against zinc oxide nanoparticle induced toxicity in Caenorhabditis elegansContact CEH NORA team at noraceh@ceh.ac.ukThe NERC and CEH trademarks and logos ('the Trademarks') are registered trademarks of NERC in the UK and other countries, and may not be used without the prior written consent of the Trademark owner. suggesting that the nominal exposure to pure ZnONPs represents in vivo, at best, a mixture exposure of ionic zinc and nanoparticles. Nevertheless, the analyzes provided evidence that the metallothioneins (mtl-1 and mtl-2), the pytochelatin synthase (pcs-1) and an apoptotic marker (cep-1) were transcriptionally activated. In addition, the DCFH-DA assay provided in vitro evidence of the oxidative potential of ZnONPs in the metal exposure sensitive triple mutant.Raman spectroscopy highlighted that the biomolecular phenotype changes significantly in the metal sensitive knockout worm upon ZnONP exposure, suggesting that these metalloproteins are instrumental in the protection against cytotoxic damage. Finally, ZnONP exposure was shown to decrease growth and development, reproductive capacity and lifespan, effects which were amplified in the triple knockout. By combining diverse toxicological strategies, we identified that individuals (genotypes) housing mutations in key metalloproteins are more susceptible to ZnONP exposure, which underlines the importance of fully functional metalloproteins to minimize ZnONP induced toxicity.

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“…Perhaps the most intriguing question arises from the parallels between p53 and FoxO (van der Horst and Burgering, 2007). In the above study, inhibiting the upregulation of nuclear pore genes by Daf-16 blocked p53-dependent, but not independent, cell death (Pinkston-Gosse and Kenyon, 2007). In contrast to the current understanding of the role of FoxO in C. elegans, activation of p53 reduces lifespan in mouse models, but decreases cancer incidence, supporting a system of antagonistic pleiotropy (van der Horst and Burgering, 2007).…”

Section: Foxo-organismal Senescence and Longevitymentioning

confidence: 87%

Many forks in the path: cycling with FoxO

2008

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FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type-and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

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

Cited by 148 publications

References 28 publications

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Metalloproteins and phytochelatin synthase may confer protection against zinc oxide nanoparticle induced toxicity in Caenorhabditis elegans

Many forks in the path: cycling with FoxO

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