Transcriptional cooperation by the TGFbeta and Wnt signalling pathways in development and cancer
Bibliographic record
Abstract
Growth factors of Transforming factor beta (TGFbeta) and Wnt signalling pathways are secreted morphogenic factors critical to normal embryonic development in metazoan organisms. In Xenopus frogs, cortical rotation of the fertilized oocyte causes an overlap of signalling determinants of both pathways leading to synergistic induction of genes marking the Spemann organizer, the region that initiates gastrulation and specifies the anterior-to-posterior axis of the embryo. In post-natal organisms, active signalling from both pathways is found in a number of tissues, contributing to their homeostatic maintenance and proper physiology and architecture. While mutations affecting components of both pathways have been extensively documented in malignancies the TGFbeta pathway has generally been regarded as having tumour-suppressive functions, while the aberrant activation of the Wnt pathway is considered oncogenic. The work presented here first delineates the molecular mechanism of transcriptional cooperation between TGFbeta and Wnt. We show that the TGFbeta mediators Smad2, Smad3, and Smad4 physically associate with members of the LEF1/TCF family of DNA-binding transcription factors, proteins that mediate the activation of Wnt target genes via association with beta-catenin. The interaction is mediated by the Smad MH1 and MH2 domains, and the HMG-box DNA-binding domain of LEF1. Physical association of Smads and LEF1/TCFs following stimulation of the TGFbeta and Wnt pathways targets the Xtwin gene promoter, which contains binding sites for both families of proteins, causing synergistic transcriptional activation. Next, we perform a microarray screen that identified putative cooperative target genes of TGFbeta and Wnt3a signalling in mammalian cells. A subset of the genes identified were shown to be overexpressed in tumours from MMTV-Wnt1 mice as well as in intestinal adenomas from MinAPC/+ mice, two models in which the Wnt/beta-catenin pathway is activated. One target, InhibinbetaA, is strongly activated in a synergisitc fashion by TGFbeta and Wnt3a, is highly overexpressed in Wnt and Min tumours/adenomas, is also widely over-expressed in most intestinal tumours as assessed by the use of a Tumour Profiling Array. The expression of InhibinbetaA, along with that of Gpc1, another TGFbeta/Wnt target, was also highly correlated with the expression of Axin2 and cyclinD1, two well-established target of the Wnt/beta-catenin pathway.
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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".