Functional Characterisation Of Long Spliced NcRNAs
Funder
National Health and Medical Research Council
Funding Amount
$649,230.00
Summary
Genome sequencing projects suggest we only have approximately thirty thousand coding genes which was previously considered to be far too few to provide the blueprint for generation of human complexity. More surprising was the discovery that 3-5% of the genome is transcribed but not translated into protein. The function of these non-coding RNAs is unknown but hotly debated. Is it junk? Or does it play a new key role in programming development? This grant will address this question directly.
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
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less
HFP ACTIVATES PROTEOLYSIS OF POSITIVE CELL CYCLE REGULATORS TO INHIBIT CELL CYCLE PROGRESSION IN DROSOPHILA
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions bet ....Cell proliferation is essential for animal development and tissue regeneration. In order to proliferate, cells must double their DNA contents and segregate their chromosomes precisely into daughter cells. Collectively this series of events is referred to as the Cell Cycle. The cell cycle must be carefully regulated since inappropriate proliferation can cause developmental abnormalities and tumour formation in multicellular animals. Proliferation is regulated by a balanced set of interactions between two group of proteins, cell cycle activators and cell cycle inhibitors. Aberrations in cell cycle inhibitor proteins will cause excessive cell proliferation, the first step in the multi-step process of tumour development. It is important to understand the processes that normally inhibit cell proliferation, since cells undergoing more rapid cell cycles are much more likely to develop further errors in their genetic material and progress to later stage invasive tumours. This proposal focuses on a protein (FIR-Hfp) that we have shown to inhibit cell cycle progression in the vinegar fly (Drosophila Melanogaster), which is an excellent model organism for studying developmentally regulated cell proliferation. Furthermore, most cell cycle regulators are conserved in evolution, so the knowledge derived from these studies can assist with our understanding of how complex pathways might coordinate proliferation mammals. FIR-Hfp negatively regulates cell proliferation by down-regulating cycle activator proteins (dMyc and Stg). At present the mechanism for the inhibitory affect on these activators is not understood, but preliminary data suggests that FIR-Hfp might be involved in causing Stg and the dMyc activator protein (Hay) to be targeted for destruction. The aim of this project is to elucidate the mechanism by which Hfp regulates the activity of these potentially ocogenic factors, and thus gain a better understanding of the preliminary stages of tumour progression.Read moreRead less