Polo Kinase Function And The Treatment Of Drug Resistant Tumours.
Funder
National Health and Medical Research Council
Funding Amount
$559,894.00
Summary
Death from cancer often results from tumours becoming resistant to chemotherapy drugs. Some cancers, particularly the common bowel cancers, have high levels of drug resistance that seem to be caused by loss of the controls that act during normal cell division. We will assess whether a recently developed therapeutic approach will kill these drug resistant cancer cells and identify factors that can be targeted to increase the potency and specificity of the therapy.
The Molecular Mechanisms Of Abscission To Complete Cytokinesis
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This project will characterise how key cytokinesis proteins co-operatively function to complete cytokinesis. This research will increase our understanding of the cell division errors that contribute to cancer development, ultimately identifying new targets for cancer therapy.
Removal of the nucleus from red blood cells (enucleation) is essential for proper circulation of red blood cells through the microvasculature and high haemoglobin concentration in the blood. How this fundamental process is achieved is surprisingly poorly understood. Here we propose to investigate how enucleation occurs in light of enucleation being an unusual asymmetric division. These studies are likely to lead to improvements in expansion of human red blood cells in vitro for transfusions.
Molecular Control Of Cell Proliferation In Early Mouse Development
Funder
National Health and Medical Research Council
Funding Amount
$338,009.00
Summary
Elucidation of cell cycle regulation in the proliferating pluripotent cells of the early mammalian embryo is likely to have important impact on basic scientific knowledge, and on the development of novel therapeutic strategies. Investigation of this problem, in vitro and in vivo, requires specialist skills in cell cycle analysis, and experimental manipulation of mammalian embryos and pluripotent cells. This application will seek to address these fundamental issues of early development and cell p ....Elucidation of cell cycle regulation in the proliferating pluripotent cells of the early mammalian embryo is likely to have important impact on basic scientific knowledge, and on the development of novel therapeutic strategies. Investigation of this problem, in vitro and in vivo, requires specialist skills in cell cycle analysis, and experimental manipulation of mammalian embryos and pluripotent cells. This application will seek to address these fundamental issues of early development and cell proliferation using molecular approaches. The general aims will be: 1. to obtain a detailed description of cell cycles in pluripotent and differentiating cells of the mouse embryo 2. use this information to build a molecular description of cell cycle events during early embryogenesis 3. investigate the relationship between rapid cell proliferation in the embryo and pluripotencyRead moreRead less
Transcriptional And Cell Cycle Control Of Erythropoiesis By E2F4
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
The balance in the number of cells in our body is a carefully regulated process which, when disturbed, can lead to a number of life-threatening diseases such as cancer. Through genetic studies in the mouse, we previously identified E2F4 as a protein that is required for the correct number of red blood cells in the body. Lack of E2F4 results in anaemia in the mouse embryo. We have studied these mice as a model to understand how cell production in the body can be controlled. In recent studies, we ....The balance in the number of cells in our body is a carefully regulated process which, when disturbed, can lead to a number of life-threatening diseases such as cancer. Through genetic studies in the mouse, we previously identified E2F4 as a protein that is required for the correct number of red blood cells in the body. Lack of E2F4 results in anaemia in the mouse embryo. We have studied these mice as a model to understand how cell production in the body can be controlled. In recent studies, we have identified proliferation defects and in particular cell division cycle defects as the major cause for the decreased production of red blood cells in the embryo. In addition, we have utilised gene microarray technology to survey which genes change in the absence of E2F4 by comparing gene expression profiles in normal and E2F4 deficient mice. These studies have identified a large number of genes that could be molecular targets for E2F4 and whose defective expression could be ultimately responsible for the anaemia of these mice. Importantly, our data suggests a completely novel function for E2F4 in controlling the switching on of genes required for cell division. In this proposal, we describe approaches to characterise how E2F4 controls the cell division cycle to identify the exact process(es) it may control such as DNA replication or separation of chromosomes into daughter cells. We will also test our hypothesis for a novel role for E2F4 in being able to switch on genes in nucleated red blood cell. Finally, we describe gene microarray experiments and a new promoter microarray approach to close in on the molecules directly required for the E2F4 control of red blood cell production. Because defects in the E2F family of proteins or the proteins that regulate them, the retinoblastoma, pRB family, have been implicated as central for cancer development, these studies will have broad implications for therapeutic targeting of this pathway in cancer.Read moreRead less
THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are intereste ....Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer causing mutations result in up-regulation of this critical cell cycle regulator and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. We have identified a number of genes that act to negatively regulate the cell cycle, 2 of which have characteristics typical of tumour suppressors. We have identified candidate genes for 3 of these mutations, all of which encode novel proteins related to mammalian proteins involved in negative regulation of cell proliferation or tumour suppressors. In this proposal we seek to determine the way in which these proteins function to control cell proliferation in Drosophila. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is likely to be highly relevant to the control of cell proliferation and the development of cancer in humans.Read moreRead less
The mechanisms controlling cell growth are often disrupted in cancers. Here we will investigate a fundamental mechanism that ensures that every daughter cells receives identical copies of DNA. This control mechanism also appears to have a key role in protecting the cells that continuously repopulate the epidermal layer ofthe skin that are target for ultraviolet radiation induced mutation that lead to skin cancers. This mechanism is inoperative in cells derived from skin cancers, indicating that ....The mechanisms controlling cell growth are often disrupted in cancers. Here we will investigate a fundamental mechanism that ensures that every daughter cells receives identical copies of DNA. This control mechanism also appears to have a key role in protecting the cells that continuously repopulate the epidermal layer ofthe skin that are target for ultraviolet radiation induced mutation that lead to skin cancers. This mechanism is inoperative in cells derived from skin cancers, indicating that mutation of components of this mechanism must have occurred. These mutations, and the loss of this normally protective control mechanism are likely to contribute to either an increased risk of skin cancer, or to the increased malignant spread of the diseases.Read moreRead less