The role of endoplasmic reticulum BIK in p53-mediated apoptosis /
Bibliographic record
Abstract
Apoptosis is a genetically programmed highly regulated form of cellular suicide that plays an essential role in the development and tissue homeostasis of multicellular organisms. As a variety of pathological states such as cancer, autoimmune and neurodegenerative diseases can be ascribed to the deregulation of the apoptotic program, understanding the molecular mechanisms underlying this process is a necessary first step to therapeutic intervention. The BCL-2 family of proteins is of paramount importance in the regulation of apoptosis through their control of caspases, a family of cysteine proteases responsible for cellular demolition. The p53 tumour suppressor protein is a transcription factor that eliminates potentially dangerous cells via activation of the apoptotic program through the regulation of various genes, including those of the BCL-2 family. I found that BIK, a member of the pro-apoptotic BH3-only class of BCL-2 homologues, is upregulated by p53. Unlike all other BH3-only proteins however, BIK was found to be uniquely localized to membranes of the endoplasmic reticulum. BIK was induced in response to several stress stimuli, including genotoxic stress (radiation; doxorubicin) and over-expression of E1A or p53, but not by ER stress pathways resulting from protein misfolding. Using siRNA technology, I showed that BIK plays a critical role in p53-induced cell death by acting at the ER to trigger Ca2+ release, mitochondrial fission, BAX/BAK activation, cytochrome c release, caspase activation and apoptosis. BIK also stimulated the (BCL-2 inhibited) accumulation and oligomerization of BAK at ER membranes. Cells doubly deficient of both BAX and BAK were resistant to ER Ca2+ release and apoptosis by ectopic expression of both BIK and p20BAP31, suggesting that these multidomain pro-apoptotic BCL-2 proteins may serve as a common checkpoint at the ER for varying modes of stress stimuli. Thus, p53 appears to employ BIK as part of its apopto
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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 | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.014 | 0.006 |
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".