Abstract A14: Transactivation of the Rho-guanine exchange factor ARHGEF2 by oncogenic K-RAS potentiates invasion-migration in pancreatic ductal adenocarcinoma.
Bibliographic record
Abstract
Abstract Activating mutations in K-RAS are a ubiquitous feature of pancreatic ductal adenocarcinoma (PDAC). Cellular transformation by oncogenic RAS engages the MAPK pathway and involves Arhgef2, the microtubule-associated RhoGEF a potential oncogene activated downstream of oncogenic RAS. Using luciferase reporters under regulation by the human ARHGEF2 promoter, we have found that GEF-H1 is regulated by oncogenic K-RAS in multiple cell lines and is a transcriptional target of the MAPK and Jun N-terminal kinase (JNK) pathways. Treatment of cell lines with small molecule inhibitors revealed that promoter activity is dependent on MEK1/2, JNK, and TGF-beta associated kinase (TAK1). We have mapped the human ARHGEF2 promoter and found it contains three regulatory elements: a Ras responsive element (RRE), a “core” ETS transcription factor binding region and two distal PTTG binding sites. The RRE is negatively regulated by the Ras responsive element binding protein 1 (RREB1), a known oncogene regulated by oncogenic K-RAS downstream of the MAPK pathway. The ETS core region contains conserved consensus elements for AP-1, ELK1 and SP1 transcription factors (TF). The pituitary tumor-derived transforming gene (PTTG) has been implicated in PDAC tumorigenesis but its link to oncogenic K-RAS is unknown. Using RNAi and luciferase reporters with mutations in TF binding sites in the ARHGEF2 promoter, we have found the transactivation of ARHGEF2 is dependent on the ELK1 and SP1 transcription factors. Chromatin immunoprecipitation has confirmed association of these transcription factors with the endogenous ARHGEF2 promoter in multiple PDAC cell lines. Our results suggest transactivation of ARHGEF2 by oncogenic K-RAS may lead to increased RhoA activity and by extension, account for the highly metastatic potential of PDAC. Citation Format: Oliver A. Kent, Maria Jose Sandi Vargas, Robbert Rottapel. Transactivation of the Rho-guanine exchange factor ARHGEF2 by oncogenic K-RAS potentiates invasion-migration in pancreatic ductal adenocarcinoma.. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A14. doi: 10.1158/1557-3125.RASONC14-A14
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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".