Regulation of caspase activation in apoptosis: implications in pathogenesis and treatment of disease.
1. Apoptosis is an essential process to remove excess, unwanted and harmful cells and maintain homeostasis. One of the key steps in apoptosis is activation of a group of proteases termed caspases. 2. Caspases are cysteine proteases that cleave their substrates after an aspartate residue. Approximately one dozen such proteases have been cloned during the past few years. While some caspases are largely responsible for the proteolytic processing of proinflammatory cytokines, such as interleukin (IL)-1 beta, others are directly involved in the execution of apoptosis. 3. Once apoptotic upstream caspases are activated in response to specific apoptotic stimuli, they can activate the downstream or effector class of caspases. Most proteins that are cleaved during apoptosis leading to the characteristic apoptotic morphology are targeted by the downstream caspases. The cleavage of these proteins by caspases can be either an activating or inactivating event for the function of a protein; however, in most cases, it contributes to the apoptotic phenotype of the cell. 4. Because caspase cleavage is the initiating event in most forms of apoptosis, it is a tightly controlled process with many checks and balances. An understanding of the regulation of caspases is providing novel ways for therapeutic intervention to modulate apoptotic behaviour of cells in many diseases that arise due to inappropriate apoptosis. 5. The present article will endeavour to discuss recent advances in our understanding of caspase regulation and will elaborate on how this knowledge is being used in the development of new classes of therapeutic molecules that can be used for the treatment of human ailments.
Kumar
S
S
Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, Australia. sharad.kumar@imvs.sa.gov.au
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000209:etiology; D017173:Caenorhabditis elegans / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000209:etiology; D051379:Mice
D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease; D020169:Caspases