Activating Transcription Factor 3 Induces DNA Synthesis and Expression of Cyclin D1 in Hepatocytes
Bibliographic record
Abstract
Activating transcription factor 3 (ATF3) is an early response gene that is induced rapidly during in vivo situations of cellular growth such as liver regeneration. However, neither the physiological function nor the potential target genes of this transcription factor related to cellular proliferation have been identified in the liver or other tissues. We demonstrate here that endogenous ATF3 mRNA expression is rapidly induced up to 4-fold upon mitogenic stimulation of quiescent Hepa 1-6 mouse hepatoma cells. Overexpression of exogenous ATF3 results in a significant, dose-dependent increase in DNA synthesis of up to 140% over control cells. ATF3-transfected cells also display significantly higher rates of [(3)H]thymidine incorporation in comparison with nontransfected controls in the presence of serum. Northern blot analysis and co-transfection experiments demonstrate that overexpression of ATF3 enhances cyclin D1 mRNA expression and activates the cyclin D1 promoter 2.5-fold when activating protein-1 (AP-1) and cyclic AMP response element (CRE) sites within the promoter are intact. ATF3-mediated promoter activation is reduced to 1.3-fold and 1.6-fold respectively when the AP-1 or CRE sites are mutated, and mutation of both sites simultaneously leads to the complete abrogation of promoter activation. Furthermore, DNA-binding studies demonstrate that ATF3 binds directly to the AP-1 site within the cyclin D1 promoter. These results indicate that ATF3 expression stimulates hepatocellular proliferation, suggesting that this effect is mediated, at least in part, by the ATF3-dependent activation of cyclin D1 transcription.
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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 | 0.001 |
| 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".