Abstract 459: Caveolin-1 mediated signaling and proliferation is regulated through the oxygen sensing pathway
Bibliographic record
Abstract
Abstract Caveolin-1 (Cav-1) is a multifunctional scaffolding protein with multiple binding partners that is associated with cell surface caveolae and the regulation of lipid raft domains. Cav-1 regulates multiple cancer-associated processes including cellular transformation, tumour growth, cell death and survival, and multidrug resistance. A high expression of Cav-1 is found in various cancer , including clear cell renal cell carcinoma (CCRCC), correlating with large, high grade tumors and poor prognosis. However, the role of Cav-1 in the oncogenesis of CCRCC remains unclear, and its role as either an oncogene or tumour suppressor is still under debate. Here, we investigated the mechanism of Cav-1 in controlling cell proliferation using in vitro and in vivo assays. We report that Cav-1 is highly expressed in tumour compared to normal tissue in patients with CCRCC, thus Cav-1 likely functions as an oncogene. Upon knock-down of Cav-1, tumour cells (786-VHL-/-) showed a decrease in proliferation. We showed that Cav-1 is associating with EGFR, a receptor tyrosine kinase, to activate the Ras-RAF-MEK-ERK kinase pathway and induce cell proliferation. We found that Cav-1 binds to EGFR in immunoprecipitation. The Ras pathway is upregulated in cells overexpressing Cav-1 after EGF stimulation. Upon knockdown of Cav-1, the level of p-ERK, p-MEK, and p-c-Raf decreased, as well as the rate of cell proliferation. Upstream of the Ras pathway, we report that Cav-1 appears to be under the control of hypoxia-inducible factor (HIF). Under hypoxia, VHL (the principal negative regulator of HIF) is downregulated, thus leading to upregulation of HIF. We showed that under hypoxia, Cav-1 increased in 786-VHL, Hela and A431 cell lines. Similarly, cells with VHL loss (786-VHL-/-), thus high HIF level, had high levels of Cav-1. We are currently examining the role of Cav-1 in tumour growth by injecting SCID mice with either 786-VHL-/-, or Cav-1 knock-down 786-VHL-/- tumour cells. Since Cav-1 level seems to be under the control of HIF in renal, cervical and squamous carcinoma cell lines, it suggests that the oxygen sensing pathway plays a general role in controlling cell proliferation through upregulating Cav-1. Cav-1 should be considered as a target for drug design as the knock down of Cav-1 decreased cell proliferation and could potentially decrease tumour growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 459.
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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 | 0.001 | 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".