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The scientific resource for Caspase Enzymes, Caspase Substrates, Inhibitors, Assay Kits, Antibodies, Inducers, Mitochondrial related reagents and other essential Apoptosis research tools.
Caspases are a family of cysteine proteases that cleave proteins after aspartic acid residues. They are the main effectors of apoptosis or programmed cell death (PCD) and their activation leads to characteristic morphological changes of the cell such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing. Induction to commit suicide is required for proper organismal development, to remove cells that pose a threat to the organism (e.g. cell infected with virus, cancer cells), and to remove cells that have damaged DNA. Cells undergoing apoptosis are eventually removed by phagocytosis.
Initiator caspases are the first to be activated and include caspase-2, 8, 9 and 10. These cleave and activate the effector caspases (3, 6, 7), which cleave, degrade or activate other cellular proteins. Some caspases (1, 4, 5, 11, 12, 13, 14) have a specialized role in inflammation and their activation leads to the processing of pro-inflammatory cytokines.
Caspase activation can be mediated by intrinsic factors such as Bcl-2 on the mitochondrial membrane. Bcl-2 is normally found associated with Apaf-1. Damage causes Bcl-2 to disassociate from Apaf-1 leading to the release of cytochrome c into the cytosol. A new complex forms which is comprised of cytochrome c, Apaf-1, and caspase-9 (the apoptosome). Caspases-9 is cleaved and activates other caspases leading to an expanding cascade of proteolytic activity within the cell. This eventually results in the digestion of structural proteins in the cytoplasm, chromosomal DNA degradation and phagocytosis of the cell. External signals can also effect a caspase activation cascade. TNF and Fas receptors on the cell surface can be triggered upon ligand binding (TNF, Fas, certain toxins and chemicals) to cleave caspase-8 which then goes on to initiate increased proteolysis within the cell and its ultimate removal by phagocytosis.
Cell survival is dependent on the variety of factors and the appropriate balance of both positive and negative signals. For example, some positive regulatory signals include growth factors in neurons and IL-2 for lymphocyte mitosis. Negative regulatory signals include increased intracellular oxidant levels, reactive oxygen species (ROS), DNA damage by oxidants or radiation (UV, X-rays, gamma irradiation), injury due to mechanical damage or exposure to chemotherapeutic drugs and toxins, the presence of misfolded proteins, and 'death' activators (TNF, certain toxins, Fas ligand). Ultimate activation of the caspase signaling pathway will create a cascade of caspase enzymes that will cleave proteins essential for cell survival and lead to apoptosis.