Constitutive Photomorphogenesis Protein 1 homolog (COP1) sustains nuclear factor-4 alpha function in human hepatocyte models
Bibliographic record
Abstract
Abstract Constitutive Photomorphogenesis Protein 1 homolog (COP1) is a conserved E3 ligase with key roles in several biological systems. Prior work in hepatocyte derived tumors categorized COP1 as an oncogene but its role in untransformed hepatocytes remains largely unexplored. Here we have investigated the role of COP1 in primary human hepatocytes as well as in two transformed hepatocyte models, HepG2 and HuH-7 cells. Contrary to a previous report, COP1 suppression via siRNA had no noticeable impact on HepG2 and HuH-7 proliferation and was associated with contrasting rather than congruent transcriptome changes. Clustering analyses identified patterns indicative of perturbed metabolism in primary hepatocytes and HepG2 cells whereas patterns pointed to cell proliferation impacts in HuH-7 cells. In HepG2 and primary hepatocytes, COP1 suppression reduced the expression important hepatic regulators and markers, which could be restored by the introduction of a siRNA resistant COP1 transgene. COP1 downregulation reduced hepatic nuclear factor-4 alpha (HNF4A) abundance and function, as assessed by lower abundance of key HNF4A targets and reduced APOB secretion. HNF4A restoration partially rescued COP1 silencing in HepG2 cells. This study identifies COP1 as a key regulator of hepatocyte function, in part via HNF4A. COP1 was required to maintain HNF4A abundance and function in primary hepatocytes and in HepG2 cells, but not in HuH-7 cells. Lastly, by demonstrating contrasting roles of COP1 in HuH-7 and HepG2 cells, our findings also challenge previous work linking COP1 to hepatic tumorigenesis.
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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) | 0.000 | 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 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".