Abstract 1031: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src
Bibliographic record
Abstract
Abstract The signal transducer and activator of transcription-3 (Stat3) plays an important role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr-705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherins such as cadherin-11 (cad11), a cell to cell adhesion protein known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to interleukin-6 transcription and Stat3 activation. Stat3 in turn, downregulates the p53 tumor suppressor and upregulates anti-apoptotic genes, thus offering a potent survival signal. A large number of oncogenes such as activated Src-527 activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for antiapoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of cad11 downregulation upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. On the other hand, intermediate Src levels, which are the levels that are physiologically relevant, did allow cad11 expression, albeit at lower levels. Paradoxically, cells expressing high Src levels had actually lower Stat3 than cells expressing intermediate Src levels. This could be due to the observed downregulatory effect of Src upon cad11, and it demonstrates that cad11 is a more potent Stat3 activator than Src. Cad11 knockdown through shRNA expression in cells expressing intermediate Src levels, caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, it is actually also necessary for full neoplastic transformation by the Src oncogene. Citation Format: Stephanie Guy, Patrick Magee, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by activated Src. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1031. doi:10.1158/1538-7445.AM2015-1031
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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 | 0.001 | 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".