Is The Tumour Suppressor Activity Of P53 Independent Of Its Transcriptional Role?
Funder
National Health and Medical Research Council
Funding Amount
$162,920.00
Summary
To become cancerous, a cell must avoid death. As such, cancer cells often contain defects in cell death pathways which render them resistant to pro-death stimuli, including many chemotherapeutic drugs. To design new and better cancer therapies, it is essential that we understand the critical molecular processes that control cell death. This will allow the development of more effective ways to either reset, or bypass, defects in cell death pathways which have contributed to cancer formation.
I am a molecular geneticist investigating the development of cancer, the mechanisms controlling apoptosis, and how impaired apoptosis contributes to tumorigenesis and the resistance of cancer cells to therapy.
Investigating Mitochondrial Outer Membrane Permeabilization During Programmed Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$88,065.00
Summary
Cancer cells often contain defects which prevent their death. To kill cancer cells we must either reset or bypass these defects. Release of cytochrome c from mitochondria is a critical event in cell death and proteins that block this event render cells resistant to many cancer therapies. My research will determine how cytochrome c release occurs, how this event is regulated and how to kill cancer cells in which cytochrome c release is blocked.
Dissection Of The Mechanisms Of Action Of Evolutionarily Conserved Apoptotic Pathway Components
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machi ....Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machinery was Bcl-2; a protein associated with development of cancer. Despite much research since then, the way in which Bcl-2 and related proteins function is still unknown. This project capitalises on previous genetic and biochemical studies in a model genetic organism (the roundworm) to address this important issue. Animal cell death pathway components can be introduced into yeast such that activation of the introduced pathways leads to yeast death and its inhibition promotes yeast survival. We have used this approach to reconstitute the worm cell death pathway and a major mammalian apoptosis pathway in yeast. Yeast strains bearing these reconstituted pathways will be used to test functional equivalence of candidate mammalian proteins and their putative roundworm counterparts. The system will also be exploited to identify and characterise novel proteins that regulate cell death in mammals and worms. Understanding the way in which key molecules regulate apoptosis will assist in the development of diagnostic and therapeutic reagents for many diseases in which cell death regulation is perturbed. This project capitalises on the evolutionary conservation of apoptosis to characterise the mechanisms of action of important mammalian apoptotic regulators and to seek novel mammalian apoptotic pathway components. Proteins identified in this way are likely to be important apoptotic regulators, as our approach ensures that their functions are evolutionarily conserved.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in g ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in general to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. Various molecules that are involved in the execution and regulation of apoptosis are potentially excellent targets for therapeutic intervention in a number of disorders and will lead to the development of novel drugs for the treatment and prevention of many pathological conditions.Read moreRead less
Inhibition Of Retinoblastoma Protein Degradation By Interaction With The Serpin PAI-2 Via A Novel Consensus Motif
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cel ....Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cell differentiation, cell growth, and most importantly prevention of cancer development. Rb is attacked and destroyed by several viruses which causes cells to become cancerous. This grant seeks to fully understand how PAI-2 protects and interacts with Rb. We have already found a new site on Rb to which PAI-2 binds. This site is also used by other proteins in the cell as well as disease causing virus proteins. Examples of these proteins are BRCA1, a protein involved in breast cancer development, and EBNA6, a protein from Epstein Barr virus that causes glandular fever and tumours. We have also found, and seek to explore further, how PAI-2 reverses the activities of the cervical cancer causing proteins of the human papilloma virus. Although at an early stage, these studies may lead to the development of new therapeutic drugs based on PAI-2 for the treatment of various types cancers or warts caused by HPV. Analysing the activity of PAI-2 inside cells will have implications for understanding much of the confusing scientific literature on PAI-2 and will provide a better comprehension of the role of PAI-2 in inflammation, cell differentiation, wound healing and cancer. For example it has long been known that the presence of PAI-2 in cancerous tumours is linked with a better prognosis, an activity that can now be understood in terms of the PAI-2 interaction with Rb. This new understanding may lead to the development of PAI-2 based prognostic assays for cancer.Read moreRead less