Investigations ofp53 signaling: Insights of upstream and downstream regulation. 1. Conditional Chk1-knockout in T-cells. 2. Carnitine palmitoyltransferase 1C as novel target of p53
Bibliographic record
Abstract
Our current knowledge suggests that the tumour suppressor p53 is a means by which the metazoan cell responds to stress and plays a critical role in determining the cell fate in that response. By interrupting the appropriate stress response, we should expose the cell to potentially lethal stress. Intense study is currently progressing to conteract both DNA-damage stress response and metabolic stress response. These processes present very real opportunities for effective therapeutics against cancer. In response to DNA-damage, p53 stimulate concurrent strategies for ensuring that the damaged DNA is not inherited by daughter cells after cell division. These are by stalling cell proliferation at checkpoints thus activating DNA repair and by activating apoptosis. We have focused our research on Chk1, a kinase that activates p53. Because null mutation of Chk1 in mice is embryonic lethal, relatively little is known about the true cellular function of this factor. We used the Cre-loxP system and the Lck promoter to generate conditional mutant mice in which Chk1 was deleted only in the T-cell lineage. We found that loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes. Significantly, we found that Chk2-deficiency partially rescued the apoptosis in Chk1 mutant cells. Critically decreased energy storage, due to reduced nutrient supply, hypoxia, or genetic defect, will signal metabolic stress pathways in the cell. One class of enzymes by which the cell alternates between energy production and usage is the carnitine palmitoyltransferase (CPT) 1 family. Malonyl-CoA inhibits energy production by inhibiting the CPT1 family. We report that carnitine palmitoyltransferase 1 C (CPT 1 C), a poorly characterized member of this family, is a novel p53 target gene induced by hypoxia. In mouse embryonic stem (ES) cells, a loss-of-function mutation of CPT1 C results in mitochondrial swelling, lipid droplet accumulation, defective proliferation, and increased apoptosis due to spontaneous activation of the intrinsic mitochondrial pathway. Strikingly, ES cells deficient in CPT1C function succumb to spontaneous death under hypoxic and low glucose conditions. Our results indicate that p53 may protect cells from metabolic stress via induction of CPT1C.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".