Phosphorylation of murine double minute‐2 on Ser <sup>166</sup> is downstream of VEGF‐A in exercised skeletal muscle and regulates primary endothelial cell migration and <i>FoxO</i> gene expression
Bibliographic record
Abstract
We demonstrated in a previous study that murine double minute (Mdm)‐2 is essential for exercise‐induced skeletal muscle angiogenesis. In the current study, we investigated the mechanisms that regulate Mdm2 activity in response to acute exercise and identified VEGF‐A as a key stimulator of Mdm2 phosphorylation on Ser 166 (p‐Ser166‐Mdm2). VEGF‐A and p‐Ser166‐Mdm2 protein levels were measured in human and rodent muscle biopsy specimens after 1 bout of exercise. VEGF‐A‐dependent Mdm2 phosphorylation was demonstrated in vivo in mice harboring myofiber‐specific deletion of VEGF‐A (mVEGF –/– ) and in vitro in primary human and rodent endothelial cells (ECs). Exercise increased VEGF‐A and p‐Ser166‐Mdm2 protein levels respectively by 157 and 68% in human muscle vs. pre‐exercise levels. Similar results were observed in exercised rodent muscles compared to sedentary controls; however, exercise‐induced Mdm2 phosphorylation was significantly attenuated in mVEGF –/– mice. Recombinant VEGF‐A elevated p‐Ser166‐Mdm2 by 50–125% and stimulated migration by 33% in ECs when compared to untreated cells, whereas the Mdm2 antagonist Nutlin‐3a abrogated VEGF‐driven EC migration. Finally, overexpression of a Ser166‐Mdm2 phosphorylation mimetic increased EC migration, increased Mdm2 to FoxO1 binding (+55%), and decreased FoxO1‐dependent gene expression compared with ECs overexpressing WT‐Mdm2. Our results suggest that VEGF‐mediated Mdm2 phosphorylation on Ser 166 is a novel proangiogenic pathway within the skeletal muscle.—Aiken, J., Roudier, E., Ciccone, J., Drouin, G., Stromberg, A., Vojnovic, J., Olfert, I. M., Haas, T., Gustafsson, T., Grenier, G., Birot, O., Phosphorylation of murine double minute‐2 on Ser166 is downstream of VEGF‐A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. FASEB J. 30, 1120–1134 (2016). www.fasebj.org
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".