Abstract SY37-04: Bcl-2 family proteins as a paradigm for protein:protein interactions as chemotherapy targets
Bibliographic record
Abstract
Abstract Many aspects of cell signaling are regulated by protein:protein interactions including growth factor receptor signal transduction pathways, transcriptional regulatory complexes and programmed cell death. The Bcl-2 family proteins regulate programmed cell death via a series of protein:protein interactions that occur in the cytoplasm and in membranes. These interactions are regulated by the amount of the proteins, their locations and by post-translational modifications. The multi-domain pro-apoptotic Bcl-2 family members Bax and Bak directly regulate mitochondrial outer membrane permeabilization (MOMP), an event widely accepted as committing most cells to apoptosis. MOMP results from an ordered series of steps beginning with activation of one or more Bcl-2 homology 3 proteins (BH3-proteins). Once activated, BH3-proteins bind to mitochondria, directly recruit and activate Bax and the constitutively membrane bound Bak. In some cases ‘activation’ involves releasing a previously activated Bax or Bak from inhibition by an anti-apoptotic protein of the Bcl-2 family. Oligomerization of integral membrane Bax and/or Bak culminates in membrane permeabilization. The embedded together model describes these interactions as a series of dynamic equilibria that change when the proteins interact with membranes. Because of their role regulating apoptosis in cancer cells and in response to chemotherapy, Bcl-2 family proteins are attractive targets for the development of small molecule inhibitors. The rational development of small molecules requires understanding in detail the molecular interactions that regulate activity. However, studying protein:protein interactions for membrane bound proteins is fraught with difficulties. I will describe some of the challenges of studying this family of proteins and the successes and surprises that resulted from our analyzing and perturbing their interactions for a variety of Bcl-2 family proteins in live cells. I will highlight recent data that suggests new avenues to targeting Bcl-2 family protein:protein interactions therapeutically. Citation Format: David W. Andrews. Bcl-2 family proteins as a paradigm for protein:protein interactions as chemotherapy targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY37-04. doi:10.1158/1538-7445.AM2014-SY37-04
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".