WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells
Bibliographic record
Abstract
New molecular cancer treatment strategies aim to reconstitute wild-type p53 (WTp53) function in mutant p53 (MTp53)-expressing tumors as a means of resensitizing cells to chemotherapy or radiotherapy. The success of this approach may depend on whether MTp53 proteins are acting in a dominant-negative or independent gain-of-function mode. Herein, we describe an isogenic, temperature-sensitive p53 model (p53(A138V)) in p53-null human H1299 lung cancer cells in which WTp53 can be selectively coexpressed with a temperature-sensitive MTp53 allele (A138V) during initial DNA damage and subsequent DNA repair. Cells expressing MTp53 alone or coexpressing induced WTp53 and MTp53 were tested for p53 transcription, G(1) and G(2) cell cycle checkpoints, apoptosis, and long-term clonogenic survival following DNA damage. Transient transfection of WTp53 into H1299 cells, or shift-down of H1299-p53(A138V) stable transfectants to 32 degrees C to induce WTp53, led to increased p21(WAF1) expression and G(1) and G(2) arrests following DNA damage but did not increase BAX expression or apoptosis. In contrast, both transient and stable expression of the p53(A138V) mutant in p53-null H1299 cells (e.g. testing gain-of-function) at 37 degrees C blocked p21(WAF1) induction following DNA damage. Cell death was secondary to mitotic catastrophe and/or tumor cell senescence. Overexpression of WTp53 did not resensitize resistant MTp53-expressing cells to ionizing radiation, cisplatinum, or mitomycin C. Our results suggest that human MTp53 proteins can lead to resistant phenotypes independent of WTp53-mediated transcription and checkpoint control. This should be considered when using p53 as a prognostic factor and therapeutic target.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".