Regulation of Caspase Activation
Lead Research Organisation:
Institute of Cancer Research
Department Name: Division of Breast Cancer Research
Abstract
In animals, the behaviour of the cells that make up the body must be tightly controlled in time and space. Part of this control stems from a built-in ?auto-destruct mechanism?, called apoptosis. This mechanism is carried within each cell, and through it the cell is instructed to die if it becomes potentially harmful or is no longer required. In order for an animal to remain healthy, apoptosis must be tightly regulated. Indeed, numerous human diseases result from the loss of this regulation. In cancer, for example, mutated cells escape apoptosis, allowing them grow and divide inappropriately; the consequence is a tumour. On the other hand, when brain cells undergo apoptosis inappropriately, neurodegenerative disease results. Thus maintenance of the correct balance of apoptosis is vital, but the molecular mechanisms underlying this process are not well understood. Our aim, therefore, is to unravel the molecular machinery that controls apoptosis. Our work concentrates on a group of highly specialised enzymes called caspases, which function as the engines of the apoptotic programme. By elucidating how caspases become activated under normal conditions, we will gain a better understanding of how apoptosis becomes deregulated in human diseases.
Technical Summary
Abstract:
It is now clear that almost every aspect of human life is intimately enmeshed with the proper regulation of cell death, and failure in this regulation contributes to or forms the basis of most human disease pathogenesis such as cancer, autoimmune disease, neurodegenerative disorders and persistent viral infection. However, despite the identification of key players of the cell death machinery, surprisingly little is known about how caspases are activated and how this potentially catastrophic event is regulated. Although it is clear that initiator caspases are activated within macro-molecular complexes, such as the apoptosome, it remains elusive how initiator caspases are actually recruited into these caspase-activating structures.
Our preliminary data indicate that the atypical myosin Myosin-7A directly binds to initiator caspases and regulates caspase activation and cell death. The observation that loss of Myosin-7A suppresses stress-induced as well as developmentally-regulated cell death in Drosophila, has provided an unexpected clue to the mechanism of caspase activation. Here, we propose to elucidate how Myosin-7A contributes to activation of caspases and cell death. Since myosins are mechanochemical proteins that primarily serve in intracellular movements, we will investigate whether Myosin-7A influences the subcellular localisation of initiator caspases, and whether this contributes to the recruitment of initiator caspases to apoptosomes following cell death stimuli. We will map the domains required and investigate the evolutionary conservation of Myosin-7A-mediated activation of caspases. Initially we will use Drosophila as an entry point due to its reduced complexity and rapid in vivo validation. Because the core elements of the apoptotic machinery are highly conserved, our findings from Drosophila will help us to investigate the role of human Myosin-7A in regulating caspase activation.
Unravelling how Myosin-7A contributes to caspase regulation is critically important, as failure to induce cell death contributes to a variety of human diseases.
It is now clear that almost every aspect of human life is intimately enmeshed with the proper regulation of cell death, and failure in this regulation contributes to or forms the basis of most human disease pathogenesis such as cancer, autoimmune disease, neurodegenerative disorders and persistent viral infection. However, despite the identification of key players of the cell death machinery, surprisingly little is known about how caspases are activated and how this potentially catastrophic event is regulated. Although it is clear that initiator caspases are activated within macro-molecular complexes, such as the apoptosome, it remains elusive how initiator caspases are actually recruited into these caspase-activating structures.
Our preliminary data indicate that the atypical myosin Myosin-7A directly binds to initiator caspases and regulates caspase activation and cell death. The observation that loss of Myosin-7A suppresses stress-induced as well as developmentally-regulated cell death in Drosophila, has provided an unexpected clue to the mechanism of caspase activation. Here, we propose to elucidate how Myosin-7A contributes to activation of caspases and cell death. Since myosins are mechanochemical proteins that primarily serve in intracellular movements, we will investigate whether Myosin-7A influences the subcellular localisation of initiator caspases, and whether this contributes to the recruitment of initiator caspases to apoptosomes following cell death stimuli. We will map the domains required and investigate the evolutionary conservation of Myosin-7A-mediated activation of caspases. Initially we will use Drosophila as an entry point due to its reduced complexity and rapid in vivo validation. Because the core elements of the apoptotic machinery are highly conserved, our findings from Drosophila will help us to investigate the role of human Myosin-7A in regulating caspase activation.
Unravelling how Myosin-7A contributes to caspase regulation is critically important, as failure to induce cell death contributes to a variety of human diseases.
