How is Apoptosis Activated?
Apoptosis, or programmed cell death, is a crucial process for eliminating damaged or infected cells. It's triggered by internal signals (intrinsic cues) or external signals (extrinsic ligands activating specific pathways).
Apoptosis activation follows two main pathways:
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Intrinsic Pathway (Mitochondrial Pathway): This pathway is activated by internal cellular stress, such as DNA damage, oxidative stress (from reactive oxygen species – ROS), or loss of growth factors. Stress signals lead to mitochondrial dysfunction, releasing pro-apoptotic molecules that activate caspases, the enzymes responsible for executing cell death. The Bcl-2 family of proteins plays a crucial role in regulating this pathway. Some BH3 domains within these proteins can either sensitize or directly activate the mitochondrial pathway, influencing the release of these pro-apoptotic molecules (https://pubmed.ncbi.nlm.nih.gov/12242151/).
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Extrinsic Pathway (Death Receptor Pathway): This pathway is initiated by external signals, such as binding of ligands like Apo2L/TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) to death receptors (DR) 4 and 5 on the cell surface. This binding triggers a cascade of events involving the recruitment of adapter proteins and activation of initiator caspases (e.g., caspase-8), ultimately leading to cell death. Weak external signals can also activate the intrinsic pathway (https://en.wikipedia.org/wiki/Apoptosis). Both pathways converge on the activation of executioner caspases, like caspase-3 (https://www.ncbi.nlm.nih.gov/books/NBK26873/). Furthermore, the extrinsic and intrinsic pathways can interact; for instance, both can activate pannexin-1, which then contributes to the activation of the NLRP3 inflammasome (https://www.embopress.org/doi/10.15252/embj.2019101638).
Role of Caspases
Caspases, a family of proteases, are central to apoptosis execution. They are activated in a cascade, with initiator caspases (8, 9, 10) activating executioner caspases (e.g., caspase-3), which then cleave various cellular proteins, leading to dismantling of the cell (https://pmc.ncbi.nlm.nih.gov/articles/PMC2117903/). Granzyme A is another protease that can activate apoptosis independently of caspases (https://pmc.ncbi.nlm.nih.gov/articles/PMC2117903/). Recent research explores manipulating transcriptional kinases to activate apoptosis specifically in cancer cells (https://www.science.org/doi/10.1126/science.adl5361).
In Summary
Apoptosis activation is a complex process involving both intrinsic and extrinsic pathways, converging on the activation of caspases which dismantle the cell. Understanding these pathways is critical for developing therapies targeting apoptosis for various diseases, including cancer (https://www.nature.com/articles/s41586-023-06348-2).
