Corepressor-specific control of ROR [alpha] transcriptional activity mediated by a calcium-dependent pathway
Bibliographic record
Abstract
Eukaryotic gene regulation by members of the nuclear receptor superfamily is crucial for a vast array of cellular and physiological processes including development, differentiation, proliferation and homeostasis. Regulation of the transcriptional activity of nuclear receptors occurs through the exchange of corepressor and coactivator complexes in a ligand-dependent manner. However, this may not be the case for orphan nuclear receptors, including RORalpha. Instead, RORalpha orphan nuclear receptor activity is modulated by Ca 2+/calmodulin-dependent protein kinase IV (CAMKIV), through a yet undetermined mechanism, and RORalpha itself regulates the expression of genes involved in the calcium signaling pathway. In this study, we report that RORalpha transcriptional activity is modulated by CaMKIV through direct phosphorylation of CIR, a novel nuclear receptor corepressor, thereby influencing its interactions with RORalpha. CIR exhibits ligand-oblivious and nuclear receptor AF-2 specific functional properties, similar to those of previously characterized RORalpha corepressor Hr. In contrast, the corepressors CIR and Hr display differential mechanisms of repression, comprising of HDAC-dependent and independent pathways, respectively. Furthermore, the calcium-dependent regulation of RORalpha transcriptional activity occuring through modulation of CIR does not extend to Hr, illustrating corepressor specificity. Thus, the molecular mechanisms governing active repression of RORalpha transcriptional activity involve distinct repression and signal transduction pathways, representing a dual mode of nuclear receptor regulation.
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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) | 0.008 | 0.002 |
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".