Mitochondria-to-nucleus crosstalk mediated by Ets-1 in ovarian carcinoma cells
Bibliographic record
Abstract
4596 Mutations in mitochondrial DNA (mtDNA) are found in several cancer cell types, and similarly, mitochondrial dysregulation is a central feature of many cancers. The majority of proteins found in the mitochondria are encoded by nuclear genes, highlighting the importance of mitochondria-to-nucleus communication, yet still very little is known about the crosstalk between these two organelles. Recent investigations in our lab have indicated that expression of the nuclear-encoded transcription factor Ets-1 is up-regulated in C13* cells, a cisplatin-resistant variant derived from 2008 ovarian carcinoma cells. Ets-1 up-regulation in this variant appears to be due to increased reactive oxygen species. Gene microarray analysis indicated that various nuclear encoded mitochondrial proteins were down-regulated in 2008 cells, which were transfected to stably over-express Ets-1, compared to their non-transfected counterparts. RT-PCR analysis has further indicated that mitochondrial transcription factor A (mtTFA), a protein required for the maintenance of mtDNA, was also down-regulated in Ets-1 overexpressing cells. Given that mtDNA encoded proteins are essential for proper electron transport chain function, these results suggest that Ets-1 down-regulates nuclear and mitochondrial genes involved in energy generation through oxidative phosphorylation. Functional assays supported these findings, as Ets-1 over-expressing cells grown in the presence of glycolytic inhibitors had a depressed growth rate and displayed reduced oxygen consumption, suggesting a shift in energy production towards glycolysis. To investigate the mechanisms responsible for these phenotypes, the promoter activity of GABP target genes were investigated through the use of luciferase reporter assays. Preliminary results indicate that luciferase activity corresponding to ATP synthase β promoter activation is decreased in response to higher Ets-1 expression, suggesting that down-regulation of mitochondrial genes occurs through the occupation of GABP binding sites by Ets-1. Allowing a tumor cell to shift away from oxidative phosphorylation for energy production and towards glycolysis affords an obvious advantage to the cell, thus supporting tumor invasion. Ets-1 has a role in promoting this energy-switch, and in addition to the well-documented role of Ets-1 in angiogenesis and regulating proteases that degrade the extracellular matrix, this finding demonstrates the importance of Ets-1 as a predictor of neoplastic cell metastasis. (This work was supported by a Canadian Institutes of Health Research grant to G.Singh.)
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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) | 0.000 | 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) | 0.001 | 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 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".