Apoptosis Signaling

Apoptosis is a coordinated, energy-dependent process that involves the activation of a group of cysteine proteases called caspases and a cascade of events that link the initiating stimuli to programmed cell death. Caspases in apoptosis are broadly divided into initiators (caspases 2, 8, 9 and 10) and executioners (caspases 3, 6 and 7). The two main pathways of apoptosis are the intrinsic and extrinsic pathways. Each pathway requires specific triggers to initiate a cascade of molecular events that converge at the stage of caspase 3 activation. The activation of caspase 3 in turn triggers an execution pathway resulting in characteristic cytomorphological features including cell shrinkage, membrane blebbing, chromatin condensation and DNA fragmentation.The intrinsic signaling pathways that initiate apoptosis involve non-receptor-mediated intracellular signals (e.g. DNA damage, radiation) that cause changes in the inner mitochondrial membrane. The end result is a change in mitochondrial transmembrane potential and release of two main groups of pro-apoptotic proteins from the intermembrane space into the cytosol. The first group consists of cytochrome c (CYTC), SMAC/DIABLO, and the serine protease high temperature requirement protein A2 (HTRA2/OMI). These proteins activate the caspase-dependent mitochondrial pathway. CYTC binds and activates apoptotic peptidase activating factor 1(APAF-1) as well as procaspase-9, forming an apoptosome leading to caspase-9 activation. SMAC/DIABLO and HTRA2/OMI promote apoptosis by inhibiting IAP (inhibitors of apoptosis proteins) activity. The second group of pro-apoptotic proteins that are released from the mitochondria during apoptosis include AIF and endonuclease G. These translocate to the nucleus and cause DNA fragmentation. The regulation of these apoptotic mitochondrial events occurs through members of the BCL-2 family of proteins. The BCL-2 family of proteins governs mitochondrial membrane permeability and can be either pro-apoptotic or anti-apoptotic. Some of the anti-apoptotic proteins include BCL-2, BCL-X and BCL-XL while the pro-apoptotic proteins include BCL-10, BAX, BAK and BID. The main mechanism of action of the BCL-2 family of proteins is the regulation of CYTC release from the mitochondria, which in turn activates caspase 9 and eventually caspase 3.The extrinsic signaling pathways that initiate apoptosis involve transmembrane receptor-mediated interactions. These involve death receptors that are members of the tumor necrosis factor (TNF) receptor gene superfamily. The activation of these receptors triggers caspase 8 or 10 which can then activate the execution pathway. Alternatively, triggered caspase 8 or 10 could result in the activation of the pro apoptotic proteins BID or BAX (via tumor suppressor protein p53) resulting in a cross talk with the mitochondrial or intrinsic pathway of apoptosis.This pathway highlights the key molecular events involved in triggering apoptosis.