Liver toxicity and apoptosis: role of TGF-β1, cytochrome c and the apoptosome

Transforming growth factor-β₁ (TGF-β₁), is involved in controlling liver size, by inducing apoptotic cell death in hepatocytes. However the mechanism by which TGF-β₁ 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 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-β₁-induced apoptosis also occurs via the release of cytochrome c and the subsequent oligomerisation of Apaf-1 into an 700 kDa apoptosome complex. Our studies show that, even though TGF-β₁ 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.