The role of the von Hippel-Lindau tumour suppressor protein in cellular adhesion
Bibliographic record
Abstract
Proper regulation of the adhesive interactions of cells is crucial for cell growth, differentiation, and development. Pathological processes such as tumour invasion and metastasis can result from alterations in cell movement and signalling caused by deregulation of cell adhesion leading to a disruption of cell anchorage. Cell anchorage is mediated by both the interactions of cells with each other and with their environment. The von Hippel-Lindau (VHL) tumour suppressor protein regulates both the extracellular matrix (ECM) and cell-cell adhesion. Inactivation of the VHL gene is responsible for the development of VHL disease and is also the principal cause of sporadic clear-cell renal cell carcinoma (CC-RCC), the most common form of kidney cancer. VHL binds to the ECM protein fibronectin, and promotes its proper deposition in the extracellular space. In this thesis I show that phosphorylation of VHL in its N-terminal acidic domain by casein kinase 2 increases its binding to fibronectin, resulting in decreased fibronectin secretion and ultimately improper fibronectin matrix deposition. This post-translational modification of VHL is required for its tumour suppressor function as phospho-defective VHL fails to suppress tumour formation in a SCID mouse xenograft assay. Recently, VHL has been shown to promote the transcription of the adhesion molecule E-cadherin. VHL forms a multi-protein E3 ubiquitin ligase that marks a-subunits of the hypoxia inducible factor (HIF) transcription factor for degradation. HIF upregulates the transcription of E-cadherin transcriptional repressors, therefore upon VHL loss, E-cadherin expression is attenuated. The loss of E-cadherin correlates with the aggressiveness of numerous carcinomas and the worsening of patient prognosis. CC-RCC patient samples with negative VHL immunoreactivity are negative for E-cadherin staining. Here, I demonstrate that these patients have tumours with high Fuhrman grade and generally have poor prognosis. Additionally, I establish that CC-RCC patient samples with positive VHL immunoreactivity, albeit a mutant VHL, correlate with aberrant nuclear localization of E-cadherin. These patients generally have tumours with low Fuhrman grade and better prognosis. Therefore by regulating both the ECM and cell-cell adhesion, VHL is emerging as a central regulator of the invasive and metastatic phenotype of tumour cells.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".