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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Death receptor-induced cell killing
1Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157, USA. athorbur@wfubmc.edu
Abstract:
Apoptosis pathways activated by death receptors of the tumour necrosis factor (TNF) family such as Fas, TNFR1, or the TRAIL receptors DR4 and DR5 are implicated in diverse diseases. These are also the best-understood apoptosis pathways and many of our ideas about apoptosis regulation come from studying these pathways. Cell killing from such receptors occurs because of recruitment to the receptor of the adaptor protein FADD, which in turn recruits the pro form of caspase-8. Aggregation of pro-caspase-8 leads to its auto-activation and subsequent activation of effector caspases such as caspase-3. The apoptotic signal can be amplified through the mitochondria and inhibited through the action of competing molecules such as the inhibitor c-FLIP, which binds to the receptor complex in place of caspase-8. This simple mechanism explains much of the cell death that is induced by death receptors. However, recent studies indicate that we must incorporate new information into this model. Some examples that add new layers of complexity will be discussed in this review.
Insights
Death receptor-mediated apoptosis, crucial in disease, involves caspase activation. This review highlights recent findings that add complexity to the established model of programmed cell death.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Apoptosis pathways activated by death receptors, including TNF family members (Fas, TNFR1) and TRAIL receptors (DR4, DR5), are fundamental to understanding cell death regulation.
- These pathways involve adaptor proteins like FADD and caspases (e.g., pro-caspase-8, caspase-3), leading to programmed cell death.
- Inhibitors such as c-FLIP modulate these pathways by competing with caspase-8 for receptor complex binding.
Purpose of the Study:
- To review the established model of death receptor-mediated apoptosis.
- To discuss recent studies that introduce new complexities and layers to this model.
- To provide an updated perspective on apoptosis regulation via death receptors.
Main Methods:
- Literature review of studies on death receptor signaling pathways.
- Analysis of molecular mechanisms involved in apoptosis induction and regulation.
- Synthesis of current research findings to update existing models.
Main Results:
- The canonical model of death receptor-induced apoptosis via FADD and caspase-8 aggregation is well-established.
- Recent research reveals additional regulatory elements and complexities beyond the basic mechanism.
- Mitochondrial amplification and inhibitors like c-FLIP are key components influencing cell fate.
Conclusions:
- The understanding of death receptor-mediated apoptosis has evolved beyond the initial simple model.
- New findings necessitate incorporating additional factors to fully comprehend apoptosis regulation.
- Further research is crucial to integrate these complexities into a comprehensive view of cell death.
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