Abstract 4294: Using the zebrafish model to determine the role of the HACE1 tumor suppressor in apoptosis, cell proliferation and development
Bibliographic record
Abstract
Abstract HACE1 is a novel tumor suppressor gene located at human chromosome 6q21. HACE1 possesses both ankyrin repeats and a catalytically active HECT domain. HACE1 is downregulated in a variety of human cancers including Wilms’ tumor, melanoma, breast cancer, lung cancer, lymphoma, and colon cancer, thus representing a potentially broadly applicable genetic target. While HACE1 is widely expressed in human tissues, its role in normal development remains unknown. The zebrafish has established itself as a robust model for studying vertebrate development and modeling human cancers by virtue of conserved genetics and direct evaluation of gene expression through imaging afforded by transparent embryos. A zebrafish hace1 homologue has been identified. Whole mount in situ hybridization (WISH) assays with probes to the ankyrin repeats and HECT domains demonstrate expression of zebrafish hace1 in heart, brain and kidney at early developmental time points (24 hours post-fertilization (hpf) – 7 days post-fertilization (dpf)), consistent with human expression. WISH studies in wild type embryos, employing probes to the zebrafish hace1 HECT domain and cmcl2 (heart) or cdh17 (kidney), show co-localization at early developmental time points. Moreover, morpholino knockdown of hace1 in cmcl2-GFP transgenic embryos reveals severely perturbed cardiac development and function beginning at 48 hpf, further implicating this gene in normal vertebrate cardiac development. We have also generated two transgenic zebrafish lines harboring either wild type or dominant negative mutated C876S (C876S DN) human HACE1 genes with a green fluorescent protein (GFP) tag under the control of the ubiquitous β-actin promoter. Compared to wild type embryos, we observed increased apoptosis in 28 hpf C876S DN by acridine orange and caspase 3 assays, both untreated and following irradiation-induced cellular damage. There was no statistically significant difference in cellular proliferation between wild type embryos and C876S DN by 5-bromo-2-deoxyuridine (BrdU) incorporation (p=0.18). These results suggest that loss of HACE1 function alone is not sufficient to lead to a dysregulated cellular proliferation and implicate additional genetic lesions, such as p53 in tumor formation. C876S DN transgenic zebrafish are being crossed with p53 mutated zebrafish in order to determine the combined effect of both mutations on apoptosis, cell proliferation, and tumor formation. Further characterization of the HACE1 transgenic zebrafish model will serve to better our understanding of the role of human HACE1 in normal development and tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4294. doi:10.1158/1538-7445.AM2011-4294
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".