Liver toxicity and apoptosis: role of TGF-beta1, cytochrome c and the apoptosome.
Transforming growth factor-beta1 (TGF-beta1), is involved in controlling liver size, by inducing apoptotic cell death in hepatocytes. However the mechanism by which TGF-beta(1) induces caspase activation and cell death is unknown. Apoptosis can be initiated either by receptor-mediated (e.g. Fas/CD95) or non-receptor chemically mediated (stress-induced) processes. With Fas/CD95 receptor mediated cell death, a multi-protein complex (DISC) is assembled at the plasma membrane, which activates the downstream caspases and cell death. In stress-mediated apoptosis, a cytosolic DISC equivalent, the apoptosome is formed that activates the effector caspases. We have characterised this complex in THP.1 cells, and shown that this is a cytochrome c dependent process that induces the formation of an approximately 700 kDa apoptosome caspase processing complex. This is formed by oligomerisation of apoptotic protease-activating factor 1 (Apaf-1), and recruitment and processing of caspase-9. We have now shown that TGF-beta1-induced apoptosis also occurs via the release of cytochrome c and the subsequent oligomerisation of Apaf-1 into an approximately 700 kDa apoptosome complex. Our studies show that, even though TGF-beta1 induction of apoptosis is a receptor-mediated event, it operates through the mitochondrial/Apaf-1 caspase activation pathway that appears to act as a common execution pathway for many diverse apoptotic stimuli.
Cain
K
K
MRC Toxicology Unit, Hodgkin Building, University of Leicester, P.O. Box 138, Lancaster Road, LE1 9HN, Leicester, UK. kc5@le.ac.uk
Freathy
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C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1; D020169:Caspases / Q000502:physiology; D003574:Cytochrome c Group / Q000502:physiology*; D004789:Enzyme Activation; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008970:Molecular Weight; D011506:Proteins / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D011506:Proteins; D016212:Transforming Growth Factor beta; D019014:fas Receptor; D020169:Caspases