Sp1-Mediated Transcriptional Control of Fibroblast Growth Factor Receptor 4 in Sarcomas of Skeletal Muscle Lineage
Bibliographic record
Abstract
Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of differentiating and proliferative actions. FGFR4 is expressed mainly in lung, kidney, pancreas, spleen, and developing muscle. FGFR4 was found to be overexpressed in some human malignancies, where it has been implicated in their pathogenesis. Recently, FGFR4 was found to be overexpressed in pediatric rhabdomyosarcomas, based on cDNA microarray analysis. Using Northern blotting, reverse transcription-polymerase chain reaction, and Western blotting, we classified four human rhabdomyosarcoma-derived cell lines based on their relative expression of FGFR4. We defined a 214 bp (-115/+99) promoter that functioned as a minimal promoter and examined cis-DNA elements implicated in the control of expression of the FGFR4 gene in these cells. Overlapping 40- to 50-bp fragments of the minimal promoter were examined by electrophoretic mobility shift assay using nuclear extracts from cell lines with high (HS729-1015) or low (HS729-1016) FGFR4 expression. Fragment C (-65/-26) formed specific complexes with nuclear extracts from both cell lines. Fragment B (-95/-56), however, formed distinct complexes mainly with the high FGFR4-expressing HS729-1015 cells. Both fragments yielded complexes that were competed by an Sp oligonucleotide and supershifted by Sp1 and by Sp3 antibodies. Transfection of Sp1 but not Sp3 efficiently activated FGFR4 promoter activity, an effect that was significantly more pronounced in the HS729-1015 cell line than in the low FGFR4-expressing HS729-1016 cell line. Deletion of each of the two Sp-binding sites in fragments B and C resulted in loss of promoter activity. In particular, deletion of the 5' Sp-binding site in fragment B was associated with the greatest loss of activity. Sp1 protein expression correlated with FGFR4 expression in cell lines and primary human rhabdomyosarcomas. Furthermore, transfection of Sp1 and methylation inhibition was effective in inducing the endogenous FGFR4 gene in HS729-1015 cells. Our findings point to Sp1 as an important contributor to FGFR4 transcriptional control and elucidate a potential mechanism for the heterogeneous expression of FGFR4 in neoplasms derived from the same cell lineage.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".