Apoptosis, programmed cell death involved in the regulation of tissue homeostasis, has extrinsic or intrinsic pathways. In both pathways, signaling results in the activation of a family of Cys (Cysteine) Proteases, named Caspases that act in a proteolytic cascade to dismantle and remove the dying cell.

The extrinsic pathway can be triggered by cell surface receptors (death receptors) like FAS and other TNFR superfamily members and ligands or by mitochondrial response to stress. The well-characterized death receptors (DRs) include Fas and TNFR1. Others include Apo2 and Apo3. Procaspase8 is the initial caspase involved in response to death receptors. In the case of Fas, upon recruitment of cofactor FADD, Procaspase8 oligomerization drives its activation through self-cleavage. Active Caspase8 then activates downstream Caspases (Caspase3 and 7), committing the cell to Apoptosis.

The extrinsic pathway can also be activated by various forms of Cellular Stress. Stress effects that can induce Apoptosis are Gamma- and UV radiation, treatment with cytotoxic drugs such as Actinomycin D and removal of cytokines. Stress induced Apoptosis occurs by a mechanism that involves altering mitochondrial permeability and subsequent CytoC release and formation of the Apoptosome, a catalytic multiprotein platform that activates Caspase9. Activated Caspase9 then cleaves Caspase3 resulting in downstream events involved in cell death. MMP (Mitochondrial Membrane Permeabilization) is clearly a pivotal event in the progression of Apoptosis in many systems.

The Intrinsic Apoptosis pathway begins when an injury occurs within the cell. Intrinsic stresses such as Oncogenes, direct DNA damage, Hypoxia, and survival factor deprivation, can activate the Intrinsic Apoptotic pathway. p53 is a sensor of cellular stress and is a critical activator of the intrinsic pathway.

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Data source: KEGG, BioCarta