Co-operative Effect of c-Src Tyrosine Kinase and Stat3 in Activation of Hepatocyte Growth Factor Expression in Mammary Carcinoma Cells
Bibliographic record
Abstract
We have previously shown coexpression of hepatocyte growth factor (HGF) and its receptor Met in the invasive tumor front of human breast carcinomas. We have also demonstrated secretion of HGF, constitutive activation of Met, and increased invasion in a murine breast carcinoma cell line, SP1. These observations suggest the presence of an HGF autocrine loop in some breast carcinoma cells, which confers increased survival, growth, and invasiveness during tumor progression and metastasis. c-Src tyrosine kinase, which is critical in regulating the expression of many genes, is activated in SP1 carcinoma cells, as well as in most human breast cancers. We therefore examined the role of c-Src kinase in HGF expression in breast carcinoma cells. Expression of activated c-Src in SP1 cells increased transcription from the HGF promoter and expression of HGF mRNA and protein, while dominant negative c-Src had the opposite effect. Using deletion analysis, we showed that the region between -254 and -70 base pairs was required for c-Src responsiveness of the HGF promoter. This region contains two putative consensus sequences (at -110 and -149 base pairs) for the Stat3 transcription factor, which bind protein complexes containing Stat3 (but not Stat1, -5A, or -5B). Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells, as well as in a nonmalignant epithelial cell line, HC11 (HGF negative). c-Src kinase activity correspondingly increased the tyrosine 705 phosphorylation and DNA binding affinity of Stat3 (but not Stat1, -5A, or -5B). Collectively, our data indicate a cooperative effect of c-Src kinase and Stat3 in the activation of HGF transcription and protein expression in breast carcinoma cells. This process may be important in overriding the strong repression of HGF expression in nonmalignant epithelium, and thereby promote tumorigenesis.
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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".