TMOD-08. GROWTH IMPAIRMENT UNDER CONDITIONS FAVORING MITOCHONDRIAL OXIDATIVE METABOLISM IN A YEAST MODEL OF CANCER-ASSOCIATED ISOCITRATE DEHYDROGENASE MUTATION
Bibliographic record
Abstract
The use of the budding yeast Saccharomyces cerevisiae as a model system to study cancer allows for faster, more efficient elucidation of various molecular mechanisms, including mutation rate by fluctuation analysis, cell cycle analysis by flow cytometry, metabolism via growth rate analysis, and functional genomics via genomic array screening. The vast majority of low grade gliomas (LGGs) carry somatic mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes. IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) in an NADP+ dependent manner. A point mutation (R132H in IDH1 and R172H in IDH2) confers the neomorphic ability for the enzyme reduce a-KG to D-2-hydroxyglutarate (D2-HG). In S. cerevisae, the NADP+ dependent isocitrate dehydrogenases are encoded by three different genes, IDP1, IDP2 and IDP3. We have successfully generated a yeast model that carries the analogous mutation in the yeast IDP1 gene (IDP1R148H). The allele was inserted at the HO locus, which does not alter the endogenous IDP1 gene. In this way, the resulting strain carries both a wild-type and mutant allele of IDP, more closely mimicking the metabolic state of glioma cells. We have validated this insertion by PCR, sequencing, and tetrad analysis. The production of the mutant IDP1R148H protein was detected by Western blot. The IDP1R148H strain shows normal growth on glucose and galactose-containing solid media, but reduced growth on glycerol-containing solid media compared to parental or IDP1WT strains. Impaired growth of yeast when glycerol is the sole carbon source suggests a defect in mitochondrial oxidative metabolism. This observation is consistent with a previous yeast IDP1R148H model which showed extensive mitochondrial DNA loss and respiration defects. Taken together, we have developed a model of IDH-mutant LGGs in S. cerevisiae that can be further utilized to study molecular mechanisms underlying tumorigenesis of LGGs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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 source (direct Gemma or distilled Codex), 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".