Regulation Of Cell Proliferation By The Actin Cytoskeleton
Funder
National Health and Medical Research Council
Funding Amount
$607,795.00
Summary
The architecture of cells defines both their shape and function. It has been known for a long time that cell architecture controls the growth of cells and in particular their capacity to proliferate. We have identified part of the architectural system which controls this process. In this project we will establish how this works and its role in the body. This research will test whether this part of the cell�s architecture is a suitable drug target for the treatment of disorders in cell growth.
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
Characterization Of Novel Inhibitors Of G1-S Phase Progression In Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. 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 p ....Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. 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, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which 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. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal seeks to further clarify the mechanism by which the identified Cyclin E interactors regulate cell cycle progression. In addition, this proposal seeks to identify the genes encoding other cyclin E interactors, expected to be novel tumor suppressors. The expected outcome of this project is to elucidate novel genes and mechanisms that control cell proliferation in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.Read moreRead less
Differentiation Therapy Of Acute Myeloid Leukaemia: Combining RAR-agonists And G-CSF.
Funder
National Health and Medical Research Council
Funding Amount
$449,500.00
Summary
The application of cancer treatments that target specific molecules hold significant promise. However to apply these treatments detailed knowledge is required of the how the molecular targets function in cells. Our previous work using normal blood cells has identified two genes ( MAD1 and p27KIP1 ) that are required for the effects of one such targeted treatment that is aimed at the retinoic acid receptor alpha. We propose to test this treatment in mouse models of human leukaemia and in human le ....The application of cancer treatments that target specific molecules hold significant promise. However to apply these treatments detailed knowledge is required of the how the molecular targets function in cells. Our previous work using normal blood cells has identified two genes ( MAD1 and p27KIP1 ) that are required for the effects of one such targeted treatment that is aimed at the retinoic acid receptor alpha. We propose to test this treatment in mouse models of human leukaemia and in human leukemia cells grown in the laboratory. By deleting the genes for MAD1 and p27KIP1 we will determine if leukaemias lacking these genes fail to respond to treatments targeting the retinoic acid receptor alpha. We will also test if treatments that target retinoic acid receptors in combination with G-CSF, a protein that has previously been demonstrated to have anti-leukaemic activity, can work together to block growth of leukaemic and genetically modified cells. Together these studies will help define classes of leukamias that either will or will not respond to treatments aimed at retinoic acid receptor to better target future leukemia treatments.Read moreRead less
The Role Of The PRB/E2F Pathway In Erythropoiesis And Cell Cycle Control
Funder
National Health and Medical Research Council
Funding Amount
$272,036.00
Summary
Circulating blood contains two major types of cells. Red blood cells supply the oxygen required by all cells in our body to survive and white blood cells protect our body from invasion by foreign organisms. The balance in the number of these cells in our blood is a carefully regulated process which, when disturbed, can lead to a number of life-threatening blood diseases. Uncontrolled overgrowth of blood cells results in a particular type of cancer known as leukaemia. In contrast, when there is a ....Circulating blood contains two major types of cells. Red blood cells supply the oxygen required by all cells in our body to survive and white blood cells protect our body from invasion by foreign organisms. The balance in the number of these cells in our blood is a carefully regulated process which, when disturbed, can lead to a number of life-threatening blood diseases. Uncontrolled overgrowth of blood cells results in a particular type of cancer known as leukaemia. In contrast, when there is an insufficient number of red blood cells, not enough oxygen reaches cells from the brain and other vital organs and results in a condition known as anaemia. We have genetically engineered a mouse that lack the protein known as E2F4 and is unable to produce enough red blood cells and suffers from anaemia. This protein, E2F4, controls genes essential for the decision of cells to start or stop growing and multiplying. The E2F4-deficient mice therefore provide a new and powerful model to understand the mechanism by which disturbance of red blood cell numbers can lead to diseases such as leukaemia and other diseases of the blood. Identification of the genes controlled by E2F4 may provide new targets for the development of therapeutic drugs to combat these diseases.Read moreRead less
Regulators Of Cell Cycle As Therapeutic Drug-targets For Cortical Tubular Hyperplasia In Proteinuric Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Currently in Australia, it has been estimated that approximately 60 000 people suffer from chronic kidney failure (CKF). In at least 80% of people with CKF, the kidney function will continue to worsen (due to disease progression) to the point where end-stage kidney failure (ESKF) has developed. When the latter occurs daily treatment by either dialysis or kidney transplantation is mandatory for a person to survive. At present, there are nearly 10 000 patients with ESKF who are being treated by di ....Currently in Australia, it has been estimated that approximately 60 000 people suffer from chronic kidney failure (CKF). In at least 80% of people with CKF, the kidney function will continue to worsen (due to disease progression) to the point where end-stage kidney failure (ESKF) has developed. When the latter occurs daily treatment by either dialysis or kidney transplantation is mandatory for a person to survive. At present, there are nearly 10 000 patients with ESKF who are being treated by dialysis or transplantation, in Australia. Although these treatments have allowed patients to survive, they are associated with significant and unacceptable patient morbidity and mortality. Current medical treatments to reduce the disease progression of CKF (and thereby extend the time taken to reach ESKF) are non-specific, partially effective and have a variable response. Also, these treatments are NOT known to arrest the progression of CKF. To compound the overall problem even further, the number of new patients starting chronic dialysis programmes is increasing (by 6% per year). Consequently, ESKF has been described by leading authorities as a medical catastrophe of world-wide dimensions, and research into ways to reduce-arrest the progression of CKF has been recommended as an urgent priority by the Australian Kidney Foundation. In CKF, the kidneys undergo compensatory growth which is harmful and paradoxically contributes to disease progression. The aim of this research program is to advance knowledge about the molecular mechanisms of kidney growth in CKF, with specific goals of: (i) identifying new molecular targets for drug-based manipulation of kidney growth; and (ii) to test the efficacy of experimental drugs which have an ability to alter kidney growth, and thereby reduce the progression of CKF.Read moreRead less
The Melanoma Susceptibility Gene Product P16 Functions In A UV-induced Cell Cycle Checkpoint In Human Skin
Funder
National Health and Medical Research Council
Funding Amount
$204,131.00
Summary
The contribution of the ultraviolet component of sunlight to skin cancer generally, and melanoma in particular, is widely acknowledged. However, the actual mechanism by which ultraviolet radiation changes the normal skin melanocytes, the pigmented skin cells, into cancerous melanomas is unclear. Several years ago, a gene was identified that was found to be mutated in a high proportion of sporadic melanomas, and was also found to be mutated in a proportion of families with a predisposition to dev ....The contribution of the ultraviolet component of sunlight to skin cancer generally, and melanoma in particular, is widely acknowledged. However, the actual mechanism by which ultraviolet radiation changes the normal skin melanocytes, the pigmented skin cells, into cancerous melanomas is unclear. Several years ago, a gene was identified that was found to be mutated in a high proportion of sporadic melanomas, and was also found to be mutated in a proportion of families with a predisposition to developing melanoma. This melanoma susceptibility gene, p16, can act to block cells growth, thus loss of this gene function in disease could lead to uncontrolled cell growth, a hallmark of cancer. This proposal investiagtes the role of p16 in responses of normal skin cells to ultraviolet radiation. We will examine the increased levels of p16 detected in skin after exposure to low doses of ultraviolet radiation and attempt to define the growth responses of these cells to the increased p16 levels. This project will help to establish the normal role of p16 in cellular responses to ultraviolet radiation, and may also identify novel targets for diagnosis, prevention or treatment of melanoma.Read moreRead less
G2 Phase Cdk2/cyclin A Co-ordinates Multiple Pathways In G2/M Progression
Funder
National Health and Medical Research Council
Funding Amount
$302,036.00
Summary
Cell growth is a tightly regulated process that ensures the exact duplication of the entire genomic DNA followed by division of the cell into two identical daughter cells. If this strict ordering of events is in any way disrupted, the resultant daughter cells would have a different complement of DNA from their parent cell, essentially mutant cells. The cell has established a mechanism to ensure the correct ordering of these crucial events, known as the cell cycle, and mechanisms that can respond ....Cell growth is a tightly regulated process that ensures the exact duplication of the entire genomic DNA followed by division of the cell into two identical daughter cells. If this strict ordering of events is in any way disrupted, the resultant daughter cells would have a different complement of DNA from their parent cell, essentially mutant cells. The cell has established a mechanism to ensure the correct ordering of these crucial events, known as the cell cycle, and mechanisms that can respond to disruptions in this ordering and halt the normal cell cycle mechanism until the fault is rectified. These are the checkpoint controls. Checkpoint controls also respond to environmental stresses such as toxins that can damage the DNA to produce mutations. In diseases such as cancer, these checkpoint mechanisms are often faulty, allowing the cells to accumulate DNA mutations which can ultimately result in the cells becoming the aggresive, malignant tumours associated with the worst forms of this disease. Thus a detailed understanding of the cellular mechanisms involved in normal cell cycle and checkpoint control is important in not only defining the causes of these diseases at a molecular level, but may ultimately provide molecular targets for drugs that specifically destroy cancer cells by targeting the faulty checkpoint control. This proposal will investigate one component of the cell cycle mechanism, cdk2-cyclin A, which also has a major role in checkpoint control, to determine its exact role in both these important cellular growth controls.Read moreRead less
Regulation And Function Of The Protein Tyrosine Phosphatase TCPTP In Mitosis
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphata ....The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphatases play an important role in reversible protein phosphorylation and they are essential for mitosis. This grant proposal is focused on understanding the regulation and function of protein phosphatases in mitosis. Our studies will provide novel insight into processes mediating mitosis and may lead to the development of alternative strategies for treating cancer.Read moreRead less