ERK is a negative feedback regulator for IFN-γ/STAT1 signaling by promoting STAT1 ubiquitination
Bibliographic record
Abstract
BACKGROUND: We recently reported that STAT1 plays a tumor suppressor role, and ERK was inversely correlation with STAT1 expression in esophageal squamous cell carcinoma (ESCC). Here, we investigated the mechanism(s) that are responsible for the ERK regulates STAT1 in ESCC. METHODS: We performed the immunoprecipitation (IP) to detect the ubiquitin of STAT1 upon MEK transfection or U0126 treatment and co-IP to confirm the binding of STAT1 and ERK in ESCC cell lines. RESULTS: We found evidence that the ubiquitin-proteasome pathway can efficiently degrade STAT1 in ESCC cells, as MG132 treatment rapidly and dramatically increased STAT1 expression in these cells. This process is not dependent on the phosphorylation of the two important STAT1 residues, Y701 and S727, as site-directed mutagenesis of these two sites did not affect STAT1 degradation. We also found that ERK promotes proteasome degradation of STAT1, supported by the observations that pharmacologic inhibition of ERK resulted in a substantial increase of STAT1 whereas expression of constitutively active ERK further reduced the STAT1 protein level. In addition to suppressing STAT1 expression, ERK limited STAT1 signaling by decreasing the production of IFNγ. CONCLUSION: To conclude, ERK is an effective negative regulator of STAT1 signaling in ESCC, by promoting its proteasome degradation and decreasing IFNγ production. Our data further supports that targeting ERK and/or STAT1 may be useful for treating ESCC.
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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".