Model for activation of apoptosis in MM by IFNs.
Following transcriptional induction by IFNs, Apo2L binds to its receptor DR5 (or DR4) and, through an adaptor intermediate (FADD), recruits caspase 8 to the cell membrane. Following caspase 8 activation by proteolysis, Bid is cleaved and translocates to mitochondria, causing release of low levels of cyt c into the cytosol, leading to caspase 9 and 3 activation. This results in attack of the anti-apoptotic protein Bcl-2 on the mitochondrial membranes, producing a truncated Bcl-2Δ protein that causes release of more cyt c, caspase activation, and apoptosis. Bcl-xL transcriptional down-regulation is an additional mechanism by which IFNs may decrease levels of anti-apoptotic proteins, shifting the balance toward a pro-apoptotic state.
