Modulation of Hsf1 activity by novobiocin and geldanamycin
Bibliographic record
Abstract
Since Hsp90 is a known modulator of HSF1 activity, we examined the effects of two pharmacological inhibitors of Hsp90, novobiocin and geldanamycin, on HSF1 DNA-binding activity in the Xenopus oocyte model system. Novobiocin exhibits antiproliferative activity in culture cells and interacts with a C-terminal ATP-binding pocket on Hsp90, inhibiting Hsp90 autophosphorylation. Treatment of oocytes with novobiocin followed by heat shock results in a dose-dependent decrease in HSF1 DNA-binding and transcriptional activity. Immunoprecipitation experiments demonstrate novobiocin does not alter HSF1 activity through dissociation of Hsp90 from either monomeric or trimerized HSF1, suggesting that the effect of novobiocin on HSF1 is mediated through alterations in Hsp90 autophosphorylation. Geldanamycin binds the N-terminal ATPase site of Hsp90 and inhibits chaperone activity. Geldanamycin treatment of oocytes resulted in a dose-dependent increase in stability of active HSF1 trimers during submaximal heat shock and a delay in disassembly of trimers during recovery. The results suggest that Hsp90 chaperone activity is required for disassembly of HSF1 trimers. The data obtained with novobiocin suggests the C-terminal ATP-binding activity of Hsp90 is required for the initial steps of HSF1 trimerization, whereas the effects of geldanamycin suggest N-terminal ATPase and chaperone activities are required for disassembly of activated trimers. These data provide important insight into the molecular mechanisms by which pharmacological inhibitors of Hsp90 affect the heat shock response.
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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) | 0.000 | 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".