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
The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particula ....The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particular growth control. The identification of how this growth control mechanism operates in normal cells, and defining the defect in tumour cells has the potential to identify new targets for more specific and potent anti-cancer drugs. The increased specificity, i.e. destruction of only the tumour cells while have little or no effect on the surround normal body tissue, would be extremely beneficial as one of the drawbacks to conventional anti-cancer treatments is their unwanted normal tissue toxicities. This is cause of the many debilitating side effects associated with chemo and radiotherapy which can limit the clinical effectiveness of these treatments.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
Normal healthy cells reproduce themselves with a remarkable fidelity. This ensures the stable inheritance of our genetic material, or DNA, and is essential for normal tissue development and maintenance. Cancer cells, on the contrary, show a high degree of rearrangements to their chromosomes, the bodies that hold the DNA. This is a result of a process known as genomic instability. This instability allows normal cells to become cancerous through the accumulation of a number of genetic changes. Thi ....Normal healthy cells reproduce themselves with a remarkable fidelity. This ensures the stable inheritance of our genetic material, or DNA, and is essential for normal tissue development and maintenance. Cancer cells, on the contrary, show a high degree of rearrangements to their chromosomes, the bodies that hold the DNA. This is a result of a process known as genomic instability. This instability allows normal cells to become cancerous through the accumulation of a number of genetic changes. This project looks at a biochemical pathway, called the G2 DNA damage checkpoint, which functions in cells to prevent cell division when the chromosomes have been damaged. Once they have been repaired, this brake is relieved, and the cells will then divide without genetic alterations. We are concentrating our studies on an enzyme, called chk1, which is the final point of this pathway. Chk1 biochemically modifies the proteins that control cell division, and stops them from carrying out their normal function when the chromosomes are damaged. Our work will determine how chk1 is told by the cell to carry out this function, and how failure to do so leads to cancer.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
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