A Yeast Mutant Screen Identifies TORC and Lys63 Polyubiquitination Pathway Genes among Determinants of Sensitivity to the Cancer Stem Cell-Specific Drug Salinomycin
Bibliographic record
Abstract
The antibiotic salinomycin (SM) acts as a selective potassium ionophore. In budding yeast (Saccharomyces cerevisiae), we describe that the agent inhibits cell growth, elevates reactive oxygen species (ROS) levels and prominently causes mitochondrial damage, as revealed by the emergence of perpetually respiration-defective cells. The collection of systematic gene deletions in haploid yeast was screened to characterize genes whose deletion confers SM sensitivity or resistance if glycerol is provided as the only carbon source, thus requiring active respiration for growth. Mutants conferring the highest SM resistance were those of the Mms2-Ubi13 E2-ubiquitin conjugating enzyme (Lys63 polyubiquitination) and the TORC pathway, such as Sch9. Sch9 phosphorylation is reduced after SM treatment and, whereas initial SM-enhanced ROS levels are not diminished in the mutant, we suggest that a protective response is mounted in the absence of Sch9 that promotes mitochondrial stability under conditions of potassium ion loss. As indicated by other isolated mutants with altered SM sensitivity, levels and modifications of ribosomal proteins may also play a role in these responses. SM has attracted considerable attention due to its cancer stem-cell specific mode of action. Even if not all of its cancer stem cell targets may have an equivalent in yeast, these studies may suggest strategies for mitigating its side effects during treatment of cancer patients.
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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) | 0.001 | 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".