Regulation of the gene encoding human thrombin-activatable fibrinolysis inhibitor by estrogen and progesterone
Bibliographic record
Abstract
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-carboxypeptidase B-like pro-enzyme that upon activation attenuates fibrinolysis and inflammatory processes. There is a large inter-individual variability in plasma TAFI levels within the population which is primarily due to epigenetic factors. Novel associations between plasma TAFI levels and sex steroids have triggered interest in determining the role of TAFI as a mediator of the cardioprotective effects of estrogens and progestins, or as a mediator of the increased thrombotic risk that accompanies use of oral contraceptives or hormone replacement therapy (HRT). In this study, we measured the effect of sex steroids on hepatic expression of CPB2, the human gene encoding TAFI. Using human hepatocellular carcinoma cells cultured in the presence of progesterone and 17β-estradiol, we demonstrated that the level of TAFI protein is decreased by those sex steroids. These changes in protein expression were paralleled by decreases in CPB2 mRNA abundance and promoter activity. We did not find evidence of estrogen or progesterone receptor binding sites in the CPB2 promoter region, suggesting that the genomic effects of progesterone and 17β-estradiol are mediated indirectly, without receptor binding to the CPB2 promoter. Indeed, we found that the effect of estrogen was independent of the estrogen receptor and was mediated through a novel signaling pathway dependent on phosphatidylinositol 3-kinase and Akt that did not involve GPR30. Our findings provide the molecular explanation for the ability of female sex steroids to decrease plasma TAFI concentrations.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".