WIP1 Enhances Tumor Formation in a Sonic Hedgehog–Dependent Model of Medulloblastoma
Bibliographic record
Abstract
BACKGROUND: A significant number of medulloblastomas (MBs) originate from abnormal activation of the sonic hedgehog/patched (SHH/PTC) signaling pathway. Although p53 deficiency enhances tumor formation in mice, inactivation of the p53 gene is seen in a minority of MBs. Wild-type p53-induced phosphatase 1 (WIP1) downregulates p53 expression and has been shown to be overexpressed in MBs. OBJECTIVE: We tested the hypothesis that overexpression of WIP1 enhances tumor formation in an SHH-dependent model of MB. METHODS: We used the RCAS/Ntv-a system to study the effect of WIP1 in vitro and in vivo. We transfected A375-TVA cells with RCAS-WIP1 and then exposed these cells to cisplatin to determine the effect on p53 expression. We modeled ectopic WIP1 expression independently and in combination with SHH in the cerebella of newborn mice to assess the effect on tumor formation. Mice were observed for 12 weeks or until neurological symptoms developed. The brains were examined for tumor formation. RESULTS: A375-TVA cells infected with RCAS-WIP1 demonstrated reduced p53 expression after exposure to cisplatin compared with controls. We detected tumors in 12 of 35 mice (34%) injected with RCAS-WIP1 and RCAS-SHH. Tumors were detected in 3 of 40 mice (8%) injected with RCAS-SHH alone. The difference in tumor formation rates was significant (χ(2) test, P = < .01). Tumors did not form in mice injected with RCAS-WIP1 alone. CONCLUSION: We show that ectopic expression of WIP1 cooperates with SHH to enhance formation of MB, although it is insufficient to induce tumors independently. Our results verify the role of WIP1 in MB formation and provide a crucial link to the inactivation of p53 in MBs.
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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) | 0.000 | 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 | 0.000 |
| 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".