Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity

Cui, Yuxia; McBride, Sandra J.; Boyd, Windy A.; Alper, Scott; Freedman, Jonathan H.

doi:10.1186/gb-2007-8-6-r122

Cited by 159 publications

(147 citation statements)

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“…To test whether the loss of ELT-2 is mediated by B. pseudomallei infection rather than an indirect consequence of general stress, we exposed JM90 to cadmium, a toxic heavy metal known to induce stress responses in C. elegans (22). No loss of nuclear GFP was observed even with a high concentration of cadmium (50 mM) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Burkholderia pseudomallei is a Gram-negative soil bacterium that infects both humans and animals. Although cell culture studies have revealed significant insights into factors contributing to virulence and host defense, the interactions between this pathogen and its intact host remain to be elucidated. To gain insights into the host defense responses to B. pseudomallei infection within an intact host, we analyzed the genome-wide transcriptome of infected Caenorhabditis elegans and identified ∼6% of the nematode genes that were significantly altered over a 12-h course of infection. An unexpected feature of the transcriptional response to B. pseudomallei was a progressive increase in the proportion of down-regulated genes, of which ELT-2 transcriptional targets were significantly enriched. ELT-2 is an intestinal GATA transcription factor with a conserved role in immune responses. We demonstrate that B. pseudomallei down-regulation of ELT-2 targets is associated with degradation of ELT-2 protein by the host ubiquitin-proteasome system. Degradation of ELT-2 requires the B. pseudomallei type III secretion system. Together, our studies using an intact host provide evidence for pathogen-mediated host immune suppression through the destruction of a host transcription factor.innate immunity | ubiquitin-proteosomal system

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Section: Resultsmentioning

confidence: 99%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…S3B). To test whether the gcy-8 mutant animals were deficient in their ability to mount any stress-inducible transcriptional response, we exposed animals to another stress, the transition metal cadmium (15), and assayed their ability to activate transcription of two cadmium-responsive genes: hsp70 (C12C8.1) and cdr-1 (15). In contrast to what was observed upon heat shock, both hsp70 and cdr-1 mRNA were similarly increased in wild-type and gcy-8 mutant animals (Fig.…”

mentioning

confidence: 99%

Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons

Prahlad

Cornelius

Morimoto

2008

Science

317

380

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Temperature pervasively affects all cellular processes. In response to a rapid increase in temperature, all cells undergo a heat shock response, an ancient and highly conserved program of stress-inducible gene expression, to reestablish cellular homeostasis. In isolated cells, the heat shock response is initiated by the presence of misfolded proteins and therefore thought to be cellautonomous. In contrast, we show that within the metazoan Caenorhabditis elegans, the heat shock response of somatic cells is not cell-autonomous but rather depends on the thermosensory neuron, AFD, which senses ambient temperature and regulates temperature-dependent behavior. We propose a model whereby this loss of cell autonomy serves to integrate behavioral, metabolic, and stress-related responses to establish an organismal response to environmental change.The heat shock response counteracts the detrimental effects of protein misfolding and aggregation that result from biochemical and environmental stresses, including increases in temperature (1, 2). This response, orchestrated by the ubiquitously expressed heat shock factor-1 (HSF-1), involves the rapid transcription of a specific set of genes encoding the cytoprotective heat shock proteins (HSPs) (1, 2). The stress-induced appearance of nonnative proteins imbalances cellular homeostasis, and the resulting shift in chaperone requirements is thought to trigger the heat shock response (1, 2). Because all these events occur at the cellular level, the heat shock response is thought to be cell-autonomous. Indeed, isolated cells in tissue culture, unicellular organisms (1, 2), and individual cells within a multicellular organism (3) can all produce a heat shock response when exposed directly to heat.Although the heat shock response is essential for the survival of cells exposed to stress, the accumulation of large amounts of HSPs can be detrimental for cell growth and division (2, 4). Therefore, although cellular autonomy in initiating this response may be beneficial for unicellular organisms and isolated cells, the uncoordinated triggering of the heat shock response in individual cells within a multicellular organism could interfere with the complex interactions between differentiated cells and tissues.In Caenorhabditis elegans, a pair of thermosensory neurons, the AFDs, detect and respond to ambient temperature (5, 6). The AFDs, and their postsynaptic partner cells, the AIYs, regulate the temperature-dependent behavior of the organism and are required for finding * To whom correspondence should be addressed. r-morimoto@northwestern.edu. the optimal temperature for growth and reproduction (6). We tested whether this thermosensory neuronal circuitry also regulates the heat shock response of somatic cells. For this, we exposed wild-type C. elegans or animals carrying loss-of-function mutations affecting the AFD or AIY neurons (Fig. 1A) to a transient increase in temperature and assayed their heat shock response. The mutations chosen {gcy-23, gcy-8 (7), tax-4, ttx-1, and ttx-3 [fo...

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“…Gene-arrays provide one obvious way to explore these stress-responses [27][28][29][30][31][32][33]. Gene-array studies of stressresponses in budding [28] and fission [29] yeasts show that overlapping stressor-specific patterns of gene regulation are the norm -superimposed on a core stress response (CSR) involving multiple metabolic genes, which is common to most stressors.…”

Section: Experimental Approachmentioning

confidence: 99%

“…We are aware that the selection of transgenic stress-reporter strains available to us is limited in scope, and that other teams have developed similar strains with proven responsiveness to particular chemical stressors. Fleshing out our transgene-based SRN with genome-wide gene-array data [27][28][29][30][31][32][33] is also vital. We see our dynamic SRN model as a resource for the entire scientific community, and all we can hope to achieve after 3 years will be a first draft, to be updated and refined in the light of future findings so that its predictions become ever more accurate.…”

Section: Community Involvement In the Srn Pro-jectmentioning

confidence: 99%

“…Gene-array studies can provide complete coverage of genome-wide changes in gene expression in response to specific stressors [e.g. [30][31][32][33], but are limited by expense, insensitivity to small changes, and sometimes poor reproducibility. Such considerations effectively preclude the routine testing of multiple stressors at different doses and time-points -let alone investigating varied combinations of such stressors.…”

Section: Experimental Approachmentioning

confidence: 99%

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The Stress-Response Network in Animals: Proposals to Develop a Predictive Mathematical Model

Pomerai¹,

Madhamshettiwar²,

Anbalagan³

et al. 2009

TOTOXIJ

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Abstract:Increasing evidence indicates that numerous genetic pathways responding to environmental stress in animals are regulated co-ordinately as well as independently. These stress-response systems should therefore be viewed in holistic terms as a network. As such, their behaviour is susceptible to mathematical modelling using a systems biology approach. This review outlines relevant evidence and describes a newly launched project to develop just such a model using stressresponse data from multiple transgenic strains of C. elegans and D. melanogaster. We hope that our eventual model will be capable of predicting the effects of simple stressor mixtures with reasonable accuracy. To maximise the effectiveness and scope of this model, we appeal for help from colleagues to share reagents and data relevant to this project. We also present preliminary data where RNA interference has implicated the key transcription factor DAF-16 in an unexpected upregulation of cyp-34A9 reporter expression by high cadmium. STRESS RESPONSES AND MIXTURE TOXICITYIn multicellular organisms, the defensive cellular responses evoked by environmental stresses do not result from simple linear pathways, but rather from a network of interlinked pathways with multiple outputs. This makes it difficult to predict the biological effects of multiple stressors acting together, even though this is the normal situation for industrial pollution of soil or water, where several different contaminants are usually present together. There are few studies and no useful predictive models describing the molecular responses of multicellular organisms to several toxicants acting in concert. This is essentially a systems biology problem, requiring integration of complex molecular and toxicological information. Under the auspices of a Major Award from the UK-India Education and Research Initiative (UK-IERI), we intend to develop an in silico model describing the principal elements of a consensus stress response network (SRN) and its in vivo responses to single stressors, using data from two invertebrate model systems, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. This model will be used to predict the likely SRN responses to stressor mixtures, and such predictions will then be tested experimentally in both species so that the model can be refined accordingly. Since the SRN core pathways are highly conserved among animal taxa, general features of this model should find wider application in ecotoxi-*Address correspondence to this author at the School of Biology, Nottingham University, Nottingham NG7 2RD, UK; Tel: (0044) 115 951 3250; Fax: (0044) 115 951 3251; E-mail: david.depomerai@nottingham.ac.uk cology. The dynamic aspects of this model, and in particular its ability to integrate multiple toxicant inputs for predicting likely SRN outputs, distinguish this from a simple map of the regulatory gene-circuits comprising the SRN. THE C. ELEGANS STRESS-RESPONSE NETWORKThe free-living soil nematode, C. elegans, is particularly suitable fo...

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Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity

Cited by 159 publications

References 63 publications

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Regulation of the Cellular Heat Shock Response in Caenorhabditis elegans by Thermosensory Neurons

The Stress-Response Network in Animals: Proposals to Develop a Predictive Mathematical Model

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