Cell density-dependent shift in activity of iron regulatory protein 1 (IRP-1)/cytosolic (c-)aconitase
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Bibliographic record
Abstract
Iron regulatory protein 1 (IRP-1) is a bifunctional protein involved in iron homeostasis and metabolism. In one state, it binds to specific sequences in the mRNA's of several proteins involved in iron and energy metabolism, thereby influencing their expression post-transcriptionally. In another state it contains a [4Fe-4S] iron-sulfur cofactor and displays aconitase activity in the cytosol. We have shown that this protein binds and hydrolyzes ATP, with kinetic and thermodynamic equilibrium constants that predict saturation with ATP, favouring a non-RNA-binding form at normal cellular ATP levels, and thus pointing to additional function(s) of the protein. Here we show for the first time that the RNA-binding and aconitase forms of IRP-1 can undergo interconversion dependent on the density of cells growing in culture. Thus, in high density confluent cultures, compared with low density, actively proliferating cultures, cytosolic aconitase activity is increased whereas RNA binding activity is diminished. This is accompanied by a decrease in transferrin receptor expression in confluent cells, possibly due to loss of the transcript-stabilizing activity of bound IRP-1. In high density HepG2 cultures, cytosolic glutamate and the ratio of reduced-to-oxidized glutathione were increased. We propose that increased cytosolic aconitase activity in confluent cultures may divert cytosolic citrate away from the fatty acid/membrane synthetic pathways required by dividing cells, into a glutamate-dependent maintenance of cellular macromolecular synthesis. In addition, this may confer additional protection from oxidative stress due to down-regulation of iron acquisition from transferrin and increased glutamate for glutathione synthesis.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 it