Characterization of novel germ line p53 mutations associated with pediatric adrenocortical cancer
Bibliographic record
Abstract
2525 Adrenocortical carcinoma (ACC) is a rare form of childhood cancer often associated with the Li-Fraumeni and Beckwith-Wiedemann syndromes. Our laboratory is interested in studying the functional properties of distinct ACC-associated p53 alterations. Five unique p53 point mutations (152L, 219S, 235D, 275ter, 337H) present in adrenocortical tumors were identified and, by means of site-directed mutagenesis, p53 sequences harboring these mutations were generated and have been analyzed in order to understand their biological properties and impact in adrenocortical cell transformation. Here we demonstrate that, with the exception of mutant p53-337H, whose activity seems to be pH-sensitive, each amino acid substitution conferred complete loss of wild-type function as shown by impaired transcriptional activity towards a p53-responsive promoter and absence of growth suppression when these p53 mutant sequences were ectopically expressed in two distinct cell lines. Moreover, three (152L, 219S, 235D) were able to act in a dominant-negative fashion abrogating p53-dependent transcriptional activity when co-transfected with wild-type p53. Currently we are exploring whether synthetic molecules including PRIMA-1, geldanamycin and others that stabilize the p53 core domain can rescue wild-type p53 function in adrenocortical cell lines. We hypothesize that the binding of chaperone molecules to these mutant proteins might be affected by these agents and understanding the mechanism by which these compounds can rescue p53 functionality may establish them as novel anticancer agents for these highly chemo-resistant tumors.
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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 | 0.001 | 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".