Abstract 4166: Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
Bibliographic record
Abstract
Abstract We report that ERK/MAPK signaling mediates tumor suppression. Oncogenic forms of ras are found in approximately 25% of all human cancers and are generally associated with uncontrolled proliferation of cancer cells. However, expression of oncogenic ras in normal cells is associated with cellular senescence. In primary cells expressing oncogenic ras, ERK knockdown by shRNA prevented the activation of the DNA damage response, p53, p16INK4a/Rb and senescence and cooperated with hTERT in transformation. In human prostate neoplasms, high levels of phosphorylated-ERK were found in benign lesions while in malignant lesions lower levels correlated with a higher Gleason score and earlier disease relapse after treatment. Mechanistically, the antitumor effects of ERK/MAPK signaling included the selective proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions and cell signaling and the inhibition of the phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling pathway. We thus show for the first time that the outcome of ERK/MAPK signaling can be controlled at the level of ERK1/2, the final members of the pathway. A quantitative control at the end of the pathway provides a mechanism for specific modulation of ERK/MAPK signaling since controlling the input may also affect the numerous signaling pathways activated by membrane receptors. The data also indicate that the levels of the ERK kinases control a binary switch between cell proliferation and senescence and explain the maintenance of the senescence phenotype despite the presence of constitutively activated growth factor signaling pathways. Since inhibitors of the ERK pathway are under consideration for clinical use, we caution that they may trigger the escape of dormant senescent cells leading to malignant tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4166. doi:1538-7445.AM2012-4166
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".