Regulation of Hedgehog signal transduction by Suppressor of fused through multiple mechanisms
Bibliographic record
Abstract
During animal development, the Hedgehog (Hh) signal transduction pathway plays a key role in multiple processes including cell fate determination, tissue patterning and morphogenesis. In humans, aberrant Hh signaling has been linked to several genetic disorders and cancers. Hh signaling is ultimately mediated through the activities of the bi-functional Gli/Ci transcription factors. Previously, the mechanism of mammalian Hh signal transduction was extrapolated largely from observations in Drosophila. In this paradigm Suppressor of fused (Su(fu)), a novel protein, inhibits pathway activity by preventing the nuclear accumulation of Ci activator, but is dispensable for development. We have previously cloned mouse Su(fu) and demonstrated it plays a conserved role to inhibit Hh signaling in vitro. Furthermore, mutations in human Su(fu) were found associated with medulloblastoma, implicating Su(fu) as a tumor suppressor. In this thesis, I employ biochemical, cell biological and genetic approaches to investigate the mechanisms through which Su(fu) inhibits activity of the mammalian Gli genes (Glil-3). I find Su(fu) controls the subcellular localization of Gli1 and Gli2 through distinct mechanisms. Moreover, Su(fu) can inhibit Gli activity independent of sequestration, suggesting Su(fu) regulates Gli activity through both nuclear and cytoplasmic means. Loss-of-function analysis in mice revealed Su(fu) is indispensable for embryogenesis, acting as a critical rate-limiting factor to control pathway activity. My genetic and biochemical analyses demonstrated a role for Su(fu) to promote efficient processing of Gli3 into a transcriptional repressor. That Su(fu) promotes Gli repressor formation was unexpected as no similar role has been identified in flies. Significantly, preliminary analyses suggest that Su(fu) controls Gli3 processing through multiple mechanisms. Most notably, Su(fu) appears to facilitate efficient cAMP-dependent protein kinase-mediated phosphorylation of Gli3. Together this work uncovers important mechanistic insight into the regulation of mammalian Hh signaling and places Su(fu) in a central role as an inhibitory component acting through several mechanisms.
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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".