Abstract 237: A novel proto-oncogene of TRIM59 characterized in mouse cancer models bridging Ras and pRb signal pathways
Bibliographic record
Abstract
Abstract Fatma Valiyeva 1, Haixing Xuan1, Fei Jiang 1, Ahmed Elmaadawi1, Siu-Pok Yee1, Madeleine Moussa1, Leda Raptis 2, Jonathan I. Izawa1, Burton B. Yang 3, Norman M. Greenberg 4, Fen Wang 5, Jim W. Xuan*1 1Lawson Heath Research Institute, University of Western Ontario, London, Ontario, Canada; 2 Queen's University, Kingston, Ontario, Canada, 3Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 4Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA, 5 Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX, USA Understanding the signal pathway network associated with Ras functions including novel effectors is critical for molecular targeted therapy, since just mutations of Ras oncogene lead to approximately 30% of all human cancers. Here we show that a novel member of the TRIM family, TRIM59, is a proto-oncogene which belongs to a new pathway linking Ras oncogene and pRB tumor suppressor. The TRIM59 gene was characterized to be up-regulated correlating with SV40Tag initiated tumorigenesis in mouse prostate cancer (CaP) models, as well as in human carcinoma. As a signal pathway effector, we identified two phosphor-forms of TRIM59 (p53 and p55), which correlated with the phosphorylation sites of Ser/Thr and Tyr as characterized in purified TRIM59 proteins in tumor samples from knock-in, and transgenic mice at different tumor stages with wild-type mice and NIH3T3 cells as controls. ELISA quantitative measurements demonstrated that the p-Tyr-TRIM59 protein correlates with advanced CaP, while p- Ser/Thr TRIM59 correlates with tumorigenesis. The function of TRIM59 was identified by shRNA knockdown in human CaP DU145 cells resulted in S-phase and cell growth retardation. Since a “hit-and-run” effect of shRNA knockdown was found only in 24 hours after transfection, differential cDNAmicroarrray was performed to identify unique signals from those of stable transfectants, which demonstrated that knockdown of TRIM59 may target the Ras signal pathway. To test the TRIM59 function as a proto-oncogene, a transgenic mouse model was established by utilizing a prostate-specific gene (PSP94) to direct up-regulation of the TRIM59 gene. In PSP94-TRIM59 mice, TRIM59 gene expression in the prostate revealed a full potential, as with SV40Tag, in inducing tumorigenesis from PIN (prostate intraductal neoplasia), from well to poorly differentiated AI (androgen independent)-NE (neuroendocrine) CaP, which coincided with the up-regulation of genes specific to the Ras signal pathway. Genes linking Ras and pRB signal pathways were identified and confirmed in tg-TRIM59 model. The finding of a novel proto-oncogene will implicate a novel strategy for diagnosis, prognosis and therapy of cancer. 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 237.
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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 | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".