Hawkins Laboratory
Department of Biochemistry
Research - Programmed Cell Death and Cancer
Apoptosis is an evolutionarily conserved, tightly regulated process that destroys surplus and dangerous cells from the body. If the regulation of apoptosis is perturbed, various diseases can result. Excessive apoptosis has been linked with degenerative diseases, while inappropriate survival can contribute to the development of cancer, infection and autoimmune disease. Defects in apoptotic pathways can also limit the efficacy of anti-cancer therapies. Chemotherapy and radiotherapy kill sensitive tumour cells largely by triggering an apoptotic response, so tumour cells with defective apoptotic pathways can be resistant to currently available anti-cancer treatments.
Our group works to characterise cell death pathways in normal, cancerous and virally infected cells. Projects encompass basic biology studies, in which apoptosis pathway components are identified and their mechanisms of action defined. In translational studies, we aim to trigger apoptosis in cells from tumours that are resistant to currently available therapies. Hopefully apoptosis-inducing agents can be developed that kill tumour cells but have less impact on normal cells and thus spare patients the adverse effects associated with currently used treatments.
Apoptosis pathway elucidation
Upon receipt of apoptotic stimuli by cells, activation of the caspase family of cysteine proteases brings about the systematic dismantling of the cell, through proteolysis of a suite of cellular substrates. We are interested in the mechanisms by which caspases are activated and their activity is regulated. We developed two yeast-based systems for identifying and characterising caspases and their substrates and regulators. The yeast Saccharomyces cerevisiae is an experimentally tractable eukaryote which, compared with other experimental systems such as mammalian and insect cell lines, lacks endogenous apoptotic signal transduction pathway components. Current projects exploit these yeast-based systems to isolate, identify and characterise novel inhibitors of caspases, Bax and Bak. Apoptosis is used to eliminate virally infected cells, and viruses express apoptosis inhibitors which prevent infected host cells from apoptosing, thus permitting the virus to replicate and infect other cells. Likewise, tumour cells evade apoptotic removal by expressing inhibitors of apoptotic pathway components. Using expression libraries from virally infected and cancerous cells, we are screening for novel cellular and viral apoptosis inhibitors. We have also reconstituted metazoan apoptotic pathways in yeast and are using these reconstituted pathways to explore the evolutionary conservation of apoptotic pathways and to define the upstream factors required for activation of caspases and the pro-apoptotic Bcl-2 relatives Bax and Bak. Other studies focus on defining the substrates of members of the caspase family.
Cancer-related projects
Although much progress has been made recently in the treatment of cancer, two general challenges remain. Some tumour types remain unresponsive to currently available therapies, so better treatments are needed. Other cancers respond well to chemotherapy and/or radiotherapy, but the treatments employed to destroy the tumour cells can also affect normal cells. This can lead to adverse effects, which sometimes include new malignancies that develop years or decades after the first cancer has been cured (so-called “late effects”). We are investigating new agents for treating incurable cancers, and are also exploring the possibility that novel apoptosis-inducing anti-cancer agents may trigger fewer or less severe late effects than chemotherapy drugs and irradiation.
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