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
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
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
Understanding The Human Hand In Grasping And How This Changes After Stroke
Funder
National Health and Medical Research Council
Funding Amount
$227,855.00
Summary
The hand allows remarkable feats of dexterity. But, paralysis of the hand severely limits daily activities and is common after stroke. We will determine key mechanisms that control the hand at the level of the brain and spinal cord. We will assess some limits that develop in the muscle itself. Stroke patients will be tested so that we can better understand the brain�s control of the hand and use this to enhance recovery of hand performance in those with impaired function.
Is Sympathetic Activation Beneficial Or Detrimental In Septic Shock?
Funder
National Health and Medical Research Council
Funding Amount
$458,755.00
Summary
Septic shock is a major cause of death in intensive care units. It is associated with large increases in sympathetic nerve activity to the heart and kidneys, which have both beneficial and harmful effects. This project will determine the responses to the increased sympathetic activity in septic shock, the causes of it and whether blocking this activation has an overall beneficial effect. This knowledge is essential before drugs that block sympathetic activation are examined in clinical studies.