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Investigating Mechanisms of BAX Acti...

Mohammed, Jarvier N.,

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Investigating Mechanisms of BAX Activation and Its Pharmacological Modulation Within the Mitochondrial Pathway of Apoptosis /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Investigating Mechanisms of BAX Activation and Its Pharmacological Modulation Within the Mitochondrial Pathway of Apoptosis // Jarvier N Mohammed.
Author:	Mohammed, Jarvier N.,
Description:	1 electronic resource (329 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
Subject:	Cellular biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30989281
ISBN:	9798381402636

Investigating Mechanisms of BAX Activation and Its Pharmacological Modulation Within the Mitochondrial Pathway of Apoptosis /
Mohammed, Jarvier N.,

Investigating Mechanisms of BAX Activation and Its Pharmacological Modulation Within the Mitochondrial Pathway of Apoptosis /Jarvier N Mohammed. - 1 electronic resource (329 pages)

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

The mitochondrial pathway of apoptosis is critical to development, homeostasis, and cancer mechanisms; and is initiated following mitochondrial outer membrane permeabilization (MOMP). MOMP allows the release of mitochondrial apoptogenic proteins, which initiate a caspase cascade in the cytosol and organized cellular dismantling. The BCL-2 family is comprised of pro- and anti-apoptotic proteins and the balance of their physical interactions governs the decision to undergo MOMP.BAX is the critical pro-apoptotic BCL-2 effector protein, which forms proteolipid pores in the outer mitochondrial membrane (OMM), allowing for MOMP to occur. In response to cellular stress, BAX is activated and undergoes a continuum of conformational changes encompassing the transition from inactive, cytosolic monomer to oligomeric pore in the OMM. While key structural hallmarks of the BAX activation continuum have been identified, current technological limitations restrict dynamic interrogations into the intra-molecular rearrangements in BAX that occur prior to membrane localization. Anti-apoptotic BCL-2 proteins neutralize pro-death signals by actively sequestering their pro-apoptotic counterparts and are typically overexpressed in cancer cells to maintain survival. BH3 mimetics competitively bind the BC groove of the anti-apoptotic repertoire, imposing enhanced cellular sensitivity to subsequent apoptotic stimuli, but acquired resistance in cancer cells has limited their efficacy. The BC groove is conserved between BAX and the anti-apoptotic repertoire, and yet, BH3 mimetics were never tested against BAX.Techniques to qualitatively and quantitatively study BAX-mediated MOMP and apoptosis were developed using isolated organelles and high-content live-cell imagers. To interrogate BAX function at the molecular level, a kinetic assay to monitor BAX activation was developed and complementary techniques were used to advance perspectives within the field on BAX activation and its regulation by pharmacological agents. Using these concepts, BH3 mimetics were revealed to target the BC groove of multiple conformations of BAX and inhibit BAX-mediated membrane permeabilization by impeding translocation to membranes.This dissertation presents several approaches to study apoptosis from single molecules to isolated organelles to cells and encompasses a variety of techniques that not only provides novel insights in BAX biology but also proposes new considerations for BH3 mimetics and their impact on multiple BCL-2 family members.

English

ISBN: 9798381402636Subjects--Topical Terms:

3172791
Cellular biology.
Subjects--Index Terms:

Apoptosis

Investigating Mechanisms of BAX Activation and Its Pharmacological Modulation Within the Mitochondrial Pathway of Apoptosis /
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520 $a The mitochondrial pathway of apoptosis is critical to development, homeostasis, and cancer mechanisms; and is initiated following mitochondrial outer membrane permeabilization (MOMP). MOMP allows the release of mitochondrial apoptogenic proteins, which initiate a caspase cascade in the cytosol and organized cellular dismantling. The BCL-2 family is comprised of pro- and anti-apoptotic proteins and the balance of their physical interactions governs the decision to undergo MOMP.BAX is the critical pro-apoptotic BCL-2 effector protein, which forms proteolipid pores in the outer mitochondrial membrane (OMM), allowing for MOMP to occur. In response to cellular stress, BAX is activated and undergoes a continuum of conformational changes encompassing the transition from inactive, cytosolic monomer to oligomeric pore in the OMM. While key structural hallmarks of the BAX activation continuum have been identified, current technological limitations restrict dynamic interrogations into the intra-molecular rearrangements in BAX that occur prior to membrane localization. Anti-apoptotic BCL-2 proteins neutralize pro-death signals by actively sequestering their pro-apoptotic counterparts and are typically overexpressed in cancer cells to maintain survival. BH3 mimetics competitively bind the BC groove of the anti-apoptotic repertoire, imposing enhanced cellular sensitivity to subsequent apoptotic stimuli, but acquired resistance in cancer cells has limited their efficacy. The BC groove is conserved between BAX and the anti-apoptotic repertoire, and yet, BH3 mimetics were never tested against BAX.Techniques to qualitatively and quantitatively study BAX-mediated MOMP and apoptosis were developed using isolated organelles and high-content live-cell imagers. To interrogate BAX function at the molecular level, a kinetic assay to monitor BAX activation was developed and complementary techniques were used to advance perspectives within the field on BAX activation and its regulation by pharmacological agents. Using these concepts, BH3 mimetics were revealed to target the BC groove of multiple conformations of BAX and inhibit BAX-mediated membrane permeabilization by impeding translocation to membranes.This dissertation presents several approaches to study apoptosis from single molecules to isolated organelles to cells and encompasses a variety of techniques that not only provides novel insights in BAX biology but also proposes new considerations for BH3 mimetics and their impact on multiple BCL-2 family members.
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650 4 $a Oncology. $3 751006
650 4 $a Pharmacology. $3 634543
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653 $a Apoptosis
653 $a BAX
653 $a BCL-2 family
653 $a Cancer
653 $a Membrane permeabilization
653 $a Therapeutics
653 $a Outer mitochondrial membrane
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710 2 $a Icahn School of Medicine at Mount Sinai. $b Cancer Biology. $e degree granting institution. $3 3770603
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