# Apoptotic Network Integrated at the Mitochondrion

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $89,400

## Abstract

Project Summary
Proper execution of cell death ensures normal biological processes, and its dysregulation
causes human illness, ranging from cancer to neurodegenerative disorders. Apoptosis is a
regulated form of cell death. Impairment of apoptosis is not only central to cancer development
but also renders tumors refractory to cytotoxic therapy. Hence, further elucidation of the
apoptotic signaling framework will not only help understand how cancer cells escape apoptotic
checkpoints but also contribute to the development of rationally designed targeted cancer
therapy. The BCL-2 family proteins govern cell death-versus-survival decisions at the
mitochondria and can be divided into three subfamilies: (1) multidomain antiapoptotic BCL-2,
BCL-XL and MCL-1; (2) multidomain proapoptotic BAX and BAK; and (3) proapoptotic BH3-only
molecules (BH3s). BH3s relay upstream apoptotic signals to promote apoptosis by either
activating BAX/BAK or inactivating BCL-2/BCL-XL/MCL-1. Genetic loss-of-function studies
reveal an essential axis of upstream “activator” BH3s and downstream BAX/BAK in activating
mitochondrion-dependent apoptosis. In response to apoptotic signals, the “activator” BH3s,
including BID, BIM and PUMA, trigger the homo-oligomerization of BAX and BAK to
permeabilize mitochondria, leading to the efflux of cytochrome c to the cytosol for caspase
activation. We recently discovered a novel mechanism by which BH3s activate BAX/BAK-
dependent mitochondrial permeabilization. We propose to elucidate this novel mechanism and
reclassify BH3s based on their mechanisms in initiating cell death. Activation of BAX/BAK by
BH3s not only triggers APAF-1-mediated caspase activation but also initiates caspase-
independent cell death. Further characterization of this novel form of cell death holds promises
for the future development of anti-cancer therapeutics that targets cancer cells with defective
caspase activation. We are also pursing whether BAX and BAK reside in different protein
complexes to differentially regulate caspase-dependent and -independent cell death programs.
Overall, our goal is to build a comprehensive proapoptotic BCl-2 signaling network in activating
mitochondrion-dependent cell death programs, which offers common ground for therapeutic
interventions.

## Key facts

- **NIH application ID:** 10005603
- **Project number:** 3R01CA125562-10S1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** EMILY H CHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $89,400
- **Award type:** 3
- **Project period:** 2007-03-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005603

## Citation

> US National Institutes of Health, RePORTER application 10005603, Apoptotic Network Integrated at the Mitochondrion (3R01CA125562-10S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10005603. Licensed CC0.

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