ArticleToxicological sciences : an official journal of the Society of Toxicology2014
Profiling dose-dependent activation of p53-mediated signaling pathways by chemicals with distinct mechanisms of DNA damage.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 43 citations in OpenAlex.
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- Genetic toxicology in silico protocol.Regulatory toxicology and pharmacology : RTP · 2019Article
- Bioflavonoids promote stable translocations between MLL-AF9 breakpoint cluster regions independent of normal chromosomal context: Model system to screen environmental risks.Environmental and molecular mutagenesis · 2019Article
- p53 induction and cell viability modulation by genotoxic individual chemicals and mixtures.Environmental science and pollution research international · 2018Article
- Loss of p53 expression in cancer cells alters cell cycle response after inhibition of exportin-1 but does not prevent cell death.Cell cycle (Georgetown, Tex.) · 2018Article
- Bridging the Data Gap FromFrontiers in public health · 2018Review
- A Qualitative Modeling Approach for Whole Genome Prediction Using High-Throughput Toxicogenomics Data and Pathway-Based Validation.Frontiers in pharmacology · 2018Article
- Time-matched analysis of DNA adduct formation and early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats.Archives of toxicology · 2017Article
- Assessment of the DNA damaging potential of environmental chemicals using a quantitative high-throughput screening approach to measure p53 activation.Environmental and molecular mutagenesis · 2017Article
- Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells.Oncotarget · 2017Article
- Adaptive Posttranslational Control in Cellular Stress Response Pathways and Its Relationship to Toxicity Testing and Safety Assessment.Toxicological sciences : an official journal of the Society of Toxicology · 2015Review
- Longitudinal tracking of single live cancer cells to understand cell cycle effects of the nuclear export inhibitor, selinexor.Scientific reports · 2015Article
- The human toxome project.ALTEX · 2015Article
- Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.Mutation research. Reviews in mutation researchReview
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As part of a larger effort to provide proof-of-concept in vitro-only risk assessments, we have developed a suite of high-throughput assays for key readouts in the p53 DNA damage response toxicity pathway: double-strand break DNA damage (p-H2AX), permanent chromosomal damage (micronuclei), p53 activation, p53 transcriptional activity, and cell fate (cell cycle arrest, apoptosis, micronuclei). Dose-response studies were performed with these protein and cell fate assays, together with whole genome transcriptomics, for three prototype chemicals: etoposide, quercetin, and methyl methanesulfonate. Data were collected in a human cell line expressing wild-type p53 (HT1080) and results were confirmed in a second p53 competent cell line (HCT 116). At chemical concentrations causing similar increases in p53 protein expression, p53-mediated protein expression and cellular processes showed substantial chemical-specific differences. These chemical-specific differences in the p53 transcriptional response appear to be determined by augmentation of the p53 response by co-regulators. More importantly, dose-response data for each of the chemicals indicate that the p53 transcriptional response does not prevent micronuclei induction at low concentrations. In fact, the no observed effect levels and benchmark doses for micronuclei induction were less than or equal to those for p53-mediated gene transcription regardless of the test chemical, indicating that p53's post-translational responses may be more important than transcriptional activation in the response to low dose DNA damage. This effort demonstrates the process of defining key assays required for a pathway-based, in vitro-only risk assessment, using the p53-mediated DNA damage response pathway as a prototype.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.