Caveolin-1 regulation of Sp1 controls production of the antifibrotic protein follistatin in kidney mesangial cells
Bibliographic record
Abstract
BACKGROUND: We previously showed that caveolin-1 (cav-1), an integral membrane protein, is required for the synthesis of matrix proteins by glomerular mesangial cells (MC). In a previous study to understand how cav-1 is involved in regulating matrix production, we had identified significant upregulation of the antifibrotic protein follistatin in cav-1 knockout MC. Follistatin inhibits the profibrotic effects of several members of the transforming growth factor beta superfamily, in particular the activins. Here, we characterize the molecular mechanism through which cav-1 regulates the expression of follistatin. METHODS: Kidneys from cav-1 wild type and knockout (KO) mice were analyzed and primary cultures of MC from cav-1 wild-type and KO mice were utilized. FST promoter deletion constructs were generated to determine the region of the promoter important for mediating FST upregulation in cav-1 KO MC. siRNA-mediated down-regulation and overexpression of Sp1 in conjunction with luciferase activity assays, immunoprecipitation, western blotting and ChiP was used to assess the role of Sp1 in transcriptionally regulating FST expression. Pharmacologic kinase inhibitors and specific siRNA were used to determine the post-translational mechanism through which cav-1 affects Sp1 activity. RESULTS: Our results establish that follistatin upregulation occurs at the transcript level. We identified Sp1 as the critical transcription factor regulating activation of the FST promoter in cav-1 KO MC through binding to a region within 123 bp of the transcription start site. We further determined that the lack of cav-1 increases Sp1 nuclear levels and transcriptional activity. This occurred through increased phosphoinositide 3-kinase (PI3K) activity and downstream protein kinase C (PKC) zeta-mediated phosphorylation and activation of Sp1. CONCLUSIONS: These findings shed light on the transcriptional mechanism by which cav-1 represses the expression of a major antifibrotic protein, and can inform the development of novel antifibrotic treatment strategies.
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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 | 0.001 |
| 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".