Molecular Mechanisms of Death-Receptor-Mediated Apoptosis

Apoptosis, also called “programmed cell death”, can be induced by a variety of stimuli including activation of death receptors by the corresponding death ligands. Death receptors are a subgroup of the tumor necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily and are characterized by a death domain, which is required for signal transduction. Upon apoptosis induction, caspases, a family of aspartyl‐specific cysteine proteases, are activated, which are the main executioners of apoptosis. Finally, specific death substrates are cleaved, resulting in the morphologic features of apoptosis. Depending on the cell type, activation of mitochondria is of central significance for apoptosis induction. This signaling pathway can be modulated by different pro‐ and anti‐apoptotic proteins such as Bax and Bcl‐2, which are localized at the mitochondria. Furthermore, apoptosis initiation can be prevented at the death receptor level by FLICE (caspase‐8)‐inhibitory proteins (FLIPs). Deregulation of apoptosis is associated with diseases like cancer, autoimmunity, and AIDS. Therefore, the elucidation of cell death pathways and the identification of modulators of apoptosis have many therapeutic implications. Both embryonic development and the onset of diseases are significantly influenced by apoptosis (also known as “programmed cell death”). The apoptosis signaling pathways have partially been elucidated, with CD95 being the best characterized death receptor (see schematic picture of the death‐inducing signaling complex, DISC). This knowledge is the basis for the development of new therapeutic strategies for the modulation of apoptosis.