The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway.
Bibliographic record
Abstract
Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein pVHL is the cause of the familial VHL disease and the majority of sporadic renal clear cell carcinomas (RCCs). RCCs pose a significant problem for conventional cancer treatment protocols because of their highly recalcitrant characteristics to radio- and/or chemotherapies. In fact, the leading cause of morbidity and mortality of VHL patients is RCC. Recently, global gene profiling of RCC cells has revealed that sensitivity to tumor necrosis factor (TNF)-alpha-mediated cytotoxicity is pVHL dependent. Here, we report that although RCC cells devoid of functional pVHL (RC3) were resistant to the cytotoxic effects of TNF-alpha, reconstitution of these RCC cells with wild-type pVHL (WT8) restored their sensitivity to TNF-alpha cytotoxicity. The major TNF-alpha-inducible transcription factor nuclear factor (NF)-kappaB in the nuclear fraction capable of binding NF-kappaB-binding motifs was significantly increased in RC3 cells. Concordantly, the expression of NF-kappaB-target antiapoptotic genes c-FLIP, Survivin, c-IAP-1, and cIAP-2, which block the activities of caspases 8 and 3, were dramatically elevated in RC3 cells. Indeed, RC3 cells showed low caspases 8 and 3 activities. These results demonstrate that pVHL facilitates TNF-alpha-induced cytotoxicity in RCC cells, at least in part, through the down-regulation of NF-kappaB activity and subsequent attenuation of antiapoptotic proteins c-FLIP, Survivin, c-IAP-1, and c-IAP-2.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".