Abstract 1713: BAX and BAK are preferentially activated by BIM and BID, respectively, affecting clinical chemotherapy response.
Notice bibliographique
Résumé
Abstract Apoptosis is a highly regulated form of cell death that is essential for maintenance of homeostasis and is controlled by the BCL-2 family of proteins. Two key members of this family, the effectors BAX and BAK, can be activated by BIM or BID, which triggers their oligomerization and permeabilization of the mitochondrial membrane, a crucial event during apoptosis. Despite their essential and distinct roles in maintaining homeostasis, BIM and BID are considered to be functionally redundant in their ability to activate BAX and BAK. However, by separately examining the activation of BAX and BAK by BIM and BID we find that these apoptosis-regulating proteins exhibit differing interaction preferences. Specifically, BIM preferentially activates BAX while BID preferentially activates BAK in murine and human cells. The preferential activation is evident when treating cells with BIM and BID BH3 peptides or recombinant, full-length proteins. Calculated EC50 values demonstrate a nearly twenty-fold decrease in the BID BH3 concentration required to activate BAK rather than BAX (0.54μM for BAK versus 9.3μM for BAX) and a three-fold decrease in the BIM BH3 concentration required to activate BAX rather than BAK (6.7μM for BAK versus 2.3μM for BAX). Based on these findings, we hypothesized that cells lacking BAK would be resistant to commonly used topoisomerase inhibitors including topotecan, etoposide and doxorubicin which can induce apoptosis via activation of BID. We confirm that BAK-/-, but not BAX-/-, cells are in fact resistant to these agents but not chemotherapies that induce apoptosis independently of BID activation including the alkylating agent cisplatin, the microtubule inhibitor paclitaxel, or the nucleoside analogue gemcitabine. Topoisomerase inhibitors are frequently used to treat ovarian cancer patients who have failed initial therapy with carboplatin and paclitaxel, yet clinical responses to these second-line therapies are varied. Importantly, we found that 23.8% of ovarian primary tumors possess a heterozygous or homozygous loss of BAK1, which encodes BAK. These patients exhibit an vastly inferior overall survival when treated with topoisomerase inhibitors in the clinic (p=0.0048) while loss of BAX had no effect on survival (p=0.9534). In addition, BAK1 loss had no effect on response to treatment with agents that were not topoisomerase inhibitors including carboplatin and paclitaxel. Thus, BIM and BID have non-overlapping roles in the induction of apoptosis via BAX and BAK which affect clinical responses to chemotherapy. Citation Format: Kristopher A. Sarosiek, John Bachman, Joan Montero, Luv Patel, Joshua J. Sims, Xiaoke Chi, David W. Andrews, Peter Sorger, Anthony Letai. BAX and BAK are preferentially activated by BIM and BID, respectively, affecting clinical chemotherapy response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1713. doi:10.1158/1538-7445.AM2013-1713
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,009 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».