SBDS-deficient cells undergo accelerated apoptosis through the Fas-pathway
Bibliographic record
Abstract
BACKGROUND: Shwachman-Diamond syndrome is an inherited multisystem disorder characterized by bone marrow and pancreatic dysfunction as well as metaphyseal dysostosis. Ninety percent of the patients have mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The relationship between SBDS and cell survival is unknown. In this study we investigated whether deficiency of the SBDS protein can cause increased apoptosis and, if so, what pathways are involved in this process. DESIGN AND METHODS: To determine whether accelerated apoptosis of Shwachman-Diamond syndrome cells is caused by a deficiency in SBDS we generated two SBDS-knockdown cell clones. We then evaluated, Fas expression and levels of the intracellular proteins, BAX, BCL-2 and BCL-X(L) and determined the effects of apoptosis inhibitors. Using oligonucteotide-microarrays we also analyzed apoptosis-related gene expression in Shwachman-Diamond syndrome marrow cells. RESULTS: We found that knocking down SBDS by short interfering hairpin RNA in HeLa cells resulted in a prominent increase in cell death. The mechanism for the accelerated apoptosis was related to marked hypersensitivity to Fas stimulation, and increased Fas expression. In contrast, there was no increase in the expression ratio of the pro-apoptotic factor, BAX, to the pro-survival factors, BCL2 and BCL-X(L) in the SBDS-knockdown cells and in the patients' marrow cells. Furthermore, inhibition of Fas and caspase 8, but not caspase 9, significantly improved the defective cell growth phenotype. CONCLUSIONS: Our work provides new data about the pro-survival properties of SBDS, whose inhibition results in accelerated apoptosis through the Fas pathway.
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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".