Abstract LB-483: p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Bibliographic record
Abstract
Abstract Cellular senescence irreversibly arrests the proliferation of cells at risk for malignant transformation in part through activities of the transcriptional regulator and tumor suppressor p53. Cells that senesce owing to DNA damage also secrete many biologically active factors, including inflammatory cytokines such as IL-6. The High Mobility Group Box 1 (HMGB1) protein is unusual in having two distinct functions. Intracellularly, it binds chromatin and modulates transcription, including stimulating p53 activity. In addition, necrosis or microbial infection causes HMGB1 leakage or active secretion, respectively, whereupon it functions as an extracellular Alarmin to signal tissue damage and promote tissue regeneration, stem cell recruitment and immune activation. We show that HMGB1 is largely nuclear in non-senescent human and mouse fibroblasts and epithelial cells, but is actively exported from the nucleus and secreted by senescent cells. In culture and in vivo, HMGB1 re-localization occurred prior to the appearance of other hallmarks of senescence, and depended on the function of p53, but not the upstream p53 activator ATM. Old mice contained significantly higher levels of HMGB1 in serum compared to young animals. Disruption of HMGB1 stoichiometry, either by overexpression or depletion, induced a p53-dependent senescence growth arrest, but only HMGB1 overexpression, not HMGB1 depletion, promoted IL-6 secretion. Senescence-associated secretion required endogenous and secreted HMGB1 because deletion of endogenous HMGB1 – or addition of an HMGB1 blocking antibody - attenuated IL-6 secretion. Recombinant HMGB1 protein induced IL-6 secretion in cells depleted, but not harboring, endogenous HMGB1. Depletion of endogenous HMGB1 promoted NF-κ B transcriptional activity in cells cultured with recombinant HMGB1. Our findings identify a novel biological setting (senescence), independent of necrosis or microbial infection, in which HMGB1 secretion occurs, and link senescence-dependent HMGB1 redistribution to p53 activity and inflammatory cytokine secretion. 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 LB-483. doi:1538-7445.AM2012-LB-483
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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 | 0.000 | 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) | 0.002 | 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".