The apoptosome: heart and soul of the cell death machine.
Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death. These central components biochemically intermingle in a ternary complex recently dubbed the "apoptosome." The C elegans protein EGL-1 and its mammalian counterparts, pro-apoptotic members of the bcl-2 family, induce cell death by disrupting apoptosome interactions. Thus, EGL-1 may represent a primordial signal integrator for the apoptosome. Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex. Recent studies suggest that cell death receptors, such as CD95, may amplify their suicide signal by activating the apoptosome. These mutual associations by core components of the suicide apparatus provide a molecular framework in which diverse death signals likely interface. Understanding the apoptosome and its cellular connections will facilitate the design of novel therapeutic strategies for cancer and other disease states in which apoptosis plays a pivotal role.
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. arul@umich.edu
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Chinnaiyan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000502:physiology; D015801:Helminth Proteins / Q000502:physiology; D006801:Humans; D012097:Repressor Proteins / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; C112486:EGL-1 protein, C elegans; D015801:Helminth Proteins; D012097:Repressor Proteins; D000255:Adenosine Triphosphate; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans