Regulation of Signal Transducer and Activator of Transcription 3 Enhanceosome Formation by Apurinic/Apyrimidinic Endonuclease 1 in Hepatic Acute Phase Response
Bibliographic record
Abstract
The signal transducer and activator of transcription-3 (STAT3) is a latent IL-6 inducible transcription factor that mediates hepatic and vascular inflammation. In this study, we make the novel observation that STAT3 forms an inducible complex with the apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (APE1/Ref-1), an essential multifunctional protein in DNA base excision repair, and studied the role of APE1/Ref-1 in STAT3 function. Using a transfection-coimmunoprecipitation assay, we observed that APE1 selectively binds the NH(2)-terminal acetylation domain of STAT3. Ectopic expression of APE1 potentiated inducible STAT3 reporter activity, whereas knockdown of APE1 resulted in reduced IL-6-inducible acute-phase reactant protein expression (C-reactive protein and serum amyloid P) and monocyte chemotactic protein-1 expression. The mechanism for APE1 requirement in IL-6 signaling was indicated by reduced STAT3 DNA binding activity observed in response to small interfering RNA-mediated APE1 silencing. Consistent with these in vitro studies, we also observed that lipopolysaccharide-induced activation of acute-phase reactant protein expression is significantly abrogated in APE1 heterozygous mice compared with wild-type mice. IL-6 induces both STAT3 and APE1 to bind the suppressor of cytokine signaling-3 and gamma-fibrionogen promoters in their native chromatin environment. Moreover, we observed that APE1 knockdown destabilized formation of the STAT3-inducible enhanceosome on the endogenous gamma-fibrionogen promoter. Taken together, our study indicates that IL-6 induces a novel STAT3-APE1 complex, whose interaction is required for stable chromatin association in the IL-6-induced hepatic acute phase response.
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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) | 0.002 | 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".