Identification of p53 Activators in a Human Microarray Compendium
Bibliographic record
Abstract
Biomarkers predictive of molecular and toxicological effects are needed to interpret emerging high-throughput transcriptomic data streams. The previously characterized 63 gene TGx-DDI biomarker that includes 20 genes known to be regulated by p53 was previously shown to accurately predict DNA damage in chemically treated cells. We comprehensively evaluated whether the molecular basis of the DDI predictions was based on a p53-dependent response. The biomarker was compared to microarray data in a compendium derived from human cells using the Running Fisher test, a nonparametric correlation test. Using the biomarker, we identified conditions that led to p53 activation, including exposure to the chemical nutlin-3 which disrupts interactions between p53 and the negative regulator MDM2 or by knockdown of MDM2. The expression of most of the genes in the biomarker (75%) were found to depend on p53 activation status based on gene behavior after TP53 overexpression or knockdown. The biomarker identified DDI chemicals that were strong inducers of p53 in wild-type cells; these p53 responses were decreased or abolished in cells after p53 knockdown by siRNAs. Using the biomarker, we screened ∼1950 chemicals in ∼9800 human cell line chemical vs control comparisons and identified ∼100 chemicals that caused p53 activation. Among the positive chemicals were many that are known to activate p53 through direct and indirect DNA damaging mechanisms. These results contribute to the evidence that the TGx-DDI biomarker is useful for identifying chemicals that cause DDI and activate p53.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".