RhoGAP mediates ceramide activation of phosphatidylglycerolphosphate synthase and drug response in Chinese hamster ovary cells
Bibliographic record
Abstract
Promoter trap mutagenesis was used to isolate an etoposide resistant CHO cell line. This resistant CHO‐K1 line, named E91, showed cross resistance to C2‐ceramide (N‐acetylsphingosine) mediated cell killing. The promoter trap retrovirus integrated into intron one‐two of the Dlc‐2 ( Stard13 ) RhoGap gene. E91 cells showed elevated GTP bound RhoA levels compared with the parental line suggesting that retrovirus integration had inactivated one of the Dlc‐2 RhoGap alleles. To test if E91 cells were impaired in an intracellular ceramide‐regulated process not directly related to cell killing, we measured mitochondrial phosphatidylglycerolphosphate (PGP) synthase and phospholipase A 2 enzyme activities in cells after C2‐ceramide addition. Parental cells showed elevated enzyme activities after treatment with C2‐ceramide or TNFα but, not the E91 cells. These results indicate that intracellular ceramide signaling was defective in E91 cells due to increased levels of active GTP bound RhoA. RNA knockdown experiments of the Dlc2 RhoGap resulted in increased GTP bound RhoA and reduced induction of PGP synthase after C2‐ceramide addition compared with controls. Expression of a dominant negative RhoA in the E91 cell line allowed induction of PGP synthase by ceramide. This study is the first report for the regulation of a phospholipid biosynthetic enzyme through a G protein. (Supported by the CIHR, NCIC, G.M.H. is a Canada Research Chair in Molecular Cardiolipin Metabolism).
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".