SIRT2 deletion enhances KRAS-induced tumorigenesis <i>in vivo</i> by regulating K147 acetylation status
Bibliographic record
Abstract
// Ha Yong Song 1 , Marco Biancucci 2 , Hong-Jun Kang 1 , Carol O’Callaghan 1 , Seong-Hoon Park 3 , Daniel R. Principe 3 , Haiyan Jiang 3 , Yufan Yan 1 , Karla Fullner Satchell 2 , Kirtee Raparia 4 , David Gius 3 and Athanassios Vassilopoulos 1 1 Department of Radiation Oncology, Laboratory for Molecular Cancer Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 2 Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 3 Department of Radiation Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 4 Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Correspondence to: Athanassios Vassilopoulos, email: // David Gius, email: // Keywords : KRAS, SIRT2, acetylation, lung cancer, pancreas transformation Received : August 23, 2016 Accepted : September 02, 2016 Published : September 13, 2016 Abstract The observation that cellular transformation depends on breaching a crucial KRAS activity threshold, along with the finding that only a small percentage of cellsharboring KRAS mutations are transformed, support the idea that additional, not fully uncovered, regulatory mechanisms may contribute to KRAS activation. Here we report that Kras G12D mice lacking Sirt2 show an aggressive tumorigenic phenotype as compared to Kras G12D mice. This phenotype includes increased proliferation, KRAS acetylation, and activation of RAS downstream signaling markers. Mechanistically, KRAS K147 is identified as a novel SIRT2-specific deacetylation target by mass spectrometry, whereas its acetylation status directly regulates KRAS activity, ultimately exerting an impact on cellular behavior as revealed by cell proliferation, colony formation, and tumor growth. Given the significance of KRAS activity as a driver in tumorigenesis, identification of K147 acetylation as a novel post-translational modification directed by SIRT2 in vivo may provide a better understanding of the mechanistic link regarding the crosstalk between non-genetic and genetic factors in KRAS driven tumors.
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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) | 0.001 | 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 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".