Apoptosis is triggered by multi-signal pathways and regulated by multi-complicated extrinsic and intrinsic ligands. The initiation of apoptosis is tightly regulated by activation mechanisms. The two best-understood activation mechanisms are the extrinsic apoptosis pathway and the intrinsic apoptosis pathway (also called the mitochondrial pathway).
The extrinsic apoptosis signaling pathways that initiate apoptosis involve transmembrane receptor-mediated interactions. These involve death receptors that are members of the tumor necrosis factor (TNF) receptor gene superfamily.
Members of the TNF receptor family share similar cyteine-rich extracellular domains and have a cytoplasmic domain of about 80 amino acids called the “death domain”. This death domain plays a critical role in transmitting the death signal from the cell surface to the intracellular signaling pathways. To date, the best-characterized ligands and corresponding death receptors include FasL/FasR, TNF-α/TNFR1, Apo3L/DR3, Apo2L/DR4 and Apo2L/DR5.
The sequence of events that define the extrinsic phase of apoptosis are best characterized with the FasL/FasR and TNF-α/TNFR1 models. In these models, there is clustering of receptors and binding with the homologous trimeric ligand.
The intrinsic apoptosis signaling pathways that initiate apoptosis involve a diverse array of non-receptor-mediated stimuli that produce intracellular signals that act directly on targets within the cell and are mitochondrial-initiated events.
The stimuli that initiate the intrinsic apoptosis signaling pathway produce intracellular signals that may act in either a positive or negative fashion. Negative signals involve the absence of certain growth factors, hormones and cytokines that can lead to failure of suppression of death programs, thereby triggering apoptosis.
In other words, there is the withdrawal of factors, loss of apoptotic suppression, and subsequent activation of apoptosis. Other stimuli that act in a positive fashion include, but are not limited to, radiation, toxins, hypoxia, hyperthermia, viral infections, and free radicals.