PTPS-29UBIQUITIN CARBOXYL TERMINAL HYDROLASE-L1 (UCH-L1) IS A TUMOR SUPPRESSOR IN ATYPICAL TERATOID RHABDOID TUMORS (ATRTs)
Bibliographic record
Abstract
BACKGROUND: Atypical teratoid rhabdoid tumor (ATRTs) constitute 20% of brain tumors in young children (<3 yrs of age) and is characterized by bi-allelic mutations of the INI-1 gene. The cell of origin in this tumor is not known and the mechanism by which INI-1 causes tumor is still not clear. Ubiquitin carboxyl-terminal hydrolase isoenzyme 1 (UCHL1), is an abundant neuronal de-ubiquitinating enzyme which acts as a tumor suppressor gene that is inactivated by promoter methylation / gene deletion in several cancers as well as an oncogene with overexpression in other cancers. The role of UCHL1 in brain tumors has not yet been studied. METHODS/RESULTS: We identified UCHL1 is silenced in ATRT cell lines (BT-12, BT-16) along with absent basal expression of p53 and NOXA by western blotting. UCHL1 silencing is mediated by promoter hyper-methylation (detected by using methylation specific PCR (MSP)); and pharmacologic de-methylation reactivated UCHL1 expression in these cell lines along with expression of p53 and NOXA. Ectopic expression of UCHL1 dramatically inhibited the growth of ATRT cell lines (using colony forming assay and MTT assay) and increased sensitivity to radiation. The growth inhibition was mediated by promoting tumor cell apoptosis resulting from activating the p53 tumor suppressor pathway. CONCLUSIONS: We have shown that UCHL1 is silenced in ATRT cell lines and acts as a tumor suppressor gene. We hypothesize that loss of p53 function due to silencing of UCHL1 drives tumor formation in the background of bi-allelic INI1 mutation in ATRT. We will further test this hypothesis using patient derived primary cell cultures and animal models (using genetically engineered mouse models INI1 +/- / UCHL1-/- mice).
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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 | 0.000 |
| 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) | 0.000 | 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".