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
Role Of Insulin-like Growth Factor Binding Protein-3 As A Mediator Of Apoptosis In Human Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$352,234.00
Summary
Human breast cancer, like other human cancers, is characterised by a disruption of normal cellular growth due to defects in the control of both cell proliferation and cell death. Understanding how these processes are regulated in normal and cancerous breast cells is an important goal for breast cancer treatment. Insulin-like growth factor binding protein (IGFBP)-3 is a regulator of normal and cancerous breast cell growth and has been implicated as a negative prognostic indicator for breast cance ....Human breast cancer, like other human cancers, is characterised by a disruption of normal cellular growth due to defects in the control of both cell proliferation and cell death. Understanding how these processes are regulated in normal and cancerous breast cells is an important goal for breast cancer treatment. Insulin-like growth factor binding protein (IGFBP)-3 is a regulator of normal and cancerous breast cell growth and has been implicated as a negative prognostic indicator for breast cancer progression. IGFBP-3 inhibits the growth of breast cancer cells and causes them to die by a process called apoptosis. We are determining how IGFBP-3 causes breast cancer cells to die by apoptosis. In particular, we are investigating whether IGFBP-3 may make breast cancer cells more sensitive to the apoptotic effects of ionising radiation and chemotherapeutic drugs which are both current therapies for the treatment of breast carcinoma. These studies may, in turn, elucidate the mechanisms that lead to increased resistance of breast cancers to these treatments.Read moreRead less
Control Of Salvador-Warts-Hippo Pathway Activity In Drosophila And Mammals
Funder
National Health and Medical Research Council
Funding Amount
$514,048.00
Summary
The primary function of the Salvador-Warts-Hippo (SWH) pathway is to dictate the appropriate size of organs in developing animals. Deregulation of this pathway results in vastly overgrown organs and can lead to the formation of cancer in humans. Our study will provide important insights into how the size of organs are controlled during development by identifying new SWH pathway components. We will also increase understanding of diseases that arise due to aberrant tissue growth, such as cancer.
Coordination Of Withdrawal From The Cell Cycle By Transcriptional Repression
Funder
National Health and Medical Research Council
Funding Amount
$271,650.00
Summary
Cancer is characterised by changes in several fundamental cellular processes including the failure of the cancer cells to stop growing in response to the body's normal stop signals.. When cells normally stop growing there is profound changes in the activity of many genes. This proposal aims to investigate how these changes in gene activity are brought about. We propose that a recently discovered family of genes called SWI-SNF work with two other families of genes (the Mad-family and Rb-family) t ....Cancer is characterised by changes in several fundamental cellular processes including the failure of the cancer cells to stop growing in response to the body's normal stop signals.. When cells normally stop growing there is profound changes in the activity of many genes. This proposal aims to investigate how these changes in gene activity are brought about. We propose that a recently discovered family of genes called SWI-SNF work with two other families of genes (the Mad-family and Rb-family) to bring about the cessation of cell growth. If our proposal is proven it will open new avenues to evaluate the growth properties of human cancers and may lead to novel strategies to inhibit cell growth.Read moreRead less
The Role Of Hox Genes In Myeloid Cell Development And Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$591,286.00
Summary
The transformation of normal white blood cells into leukaemic cells occurs as a result of changes to the genes of those cells. These changes are often characteristic of particular cancers and carry diagnostic and prognostic significance. This work will determine how critical some of the typical genetic changes of leukaemia are to the occurrence and persistence of cancer. Importantly, we will determine whether targeting these changes can provide new and effective approaches to treatment.
Using Drosophila To Define An Epithelial Cancer Stem Cell
Funder
National Health and Medical Research Council
Funding Amount
$552,988.00
Summary
Cancer is a complex disease that involves the mis-regulation of genes and aberrant cell-cell communication . To help gain a better understanding of these processes it is possible to examine simpler systems. This proposal uses a unique cancer model in flies to understand how a change in cell fate can endow cells with the ability to continue dividing and invading surrounding tissues, thus driving cancer development.
ISG60, A Novel Interferon-induced Protein: Cell Growth Inhibitory Actions
Funder
National Health and Medical Research Council
Funding Amount
$197,030.00
Summary
The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. H ....The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. However, by preparing cells which produce the ISG60 protein, we have found that it severely affects their growth, slowing the growth rate down and making the cells divide abnormally to become large, containing many nuclei and others dying. We propose that ISG60 binds to the structures involved in cell division and we have preliminary evidence that ISG60 interacts with an important protein involved in cell regulation, the retinoblastoma protein (pRb). The aim of this project is to more fully understand the role of ISG60 in cells. In particular, we aim to determine if ISG60 interacts with other important proteins inside cells. We shall explore the relationship of ISG60 function inside cells in greater detail as it should provide new insight into ways in which cell growth is regulated. This study will also provide insight into how the slowing of cell growth makes the cells less suitable for viral infection and reproduction, as well as providing new approaches for preventing the growth of cancer cells.Read moreRead less
Fission, Fusion And Distribution Of Mitochondria In Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Mitochondria are small cellular compartments that produce most of the cell's energy in the form of ATP. Mitochondria were once thought of as small bean-shaped organelles floating around in the cell, however it has become clear that this is not the case. Mitochondria are found as a network of tubules radiating from around the nucleus and they undergo constant changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules which act as highways in the ....Mitochondria are small cellular compartments that produce most of the cell's energy in the form of ATP. Mitochondria were once thought of as small bean-shaped organelles floating around in the cell, however it has become clear that this is not the case. Mitochondria are found as a network of tubules radiating from around the nucleus and they undergo constant changes in their shape through both fission and fusion events. Mitochondria are transported along microtubules which act as highways in the cell so that they can be distributed to areas that require ATP or other functions particular to mitochondria such as their ability to regulate the release of calcium. In specialist cells, mitochondria are organised even further. Sperm cells contain mitochondria packed around the mid-piece of the flagellum so that ATP can be utilised directly for swimming. Mitochondria are also highly organised in muscle cells to supply ATP for movement while in pancreatic cells mitochondria at the cell's edge help to regulate the secretion of molecules such as insulin into the bloodstream. While we are beginning to understand the great importance of mitochondria to the cell, we are yet to work out how these organelles undergo the drastic morphological changes which are essential for cellular function. In this application, we plan to identify and characterise the proteins involved in the division of mitochodria and the movement of these organelles along the microtubule highways. Understanding the basic mechanisms of mitochondrial dynamics in tissue culture cells will provide valuable insights into mitochondrial segregation and specialisation in differentiated cells such as sperm, nerve, muscle and pancreatic cells, where such events are crucial for function.Read moreRead less
Role Of The MicroRNA MiR144 In Haemopoiesis In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$392,328.00
Summary
Recently a new form of gene regulation has been discovered involving small RNA molecules called microRNAs (miRNAs). Although vertebrates (like man, mouse and fish) contain many hundreds of miRNAs, the function and true gene targets of each individual miRNA are largely unknown. A better understanding the normal function and targets of miRNAs is needed so that their role in normal biology and disease development can be understood. These studies exploit the technical strengths of zebrafish, an mode ....Recently a new form of gene regulation has been discovered involving small RNA molecules called microRNAs (miRNAs). Although vertebrates (like man, mouse and fish) contain many hundreds of miRNAs, the function and true gene targets of each individual miRNA are largely unknown. A better understanding the normal function and targets of miRNAs is needed so that their role in normal biology and disease development can be understood. These studies exploit the technical strengths of zebrafish, an model of increasing importance in biomedical research, to study the function of a particular miRNA, miR144, and to identify its physiological target genes. Zebrafish have several advantages for studying miRNA function - several simple methods for experimentally altering miRNA levels are standard in zebrafish but not easy in other models like mice. miR144 has been chosen because it has an expression pattern that strongly suggests a role in blood development. Blood development and zebrafish technologies are central themes of the Lieschke laboratory. Preliminary experiments in zebrafish have shown that miR144 expression can be detected in blood cells, that it is functionally active when overexpressed, that its effect can be intercepted, and that there are blood-system effects of its misexpression, particularly in mutant zebrafish with abnormalities of blood development that provide a sensitized background for such studies. These studies will describe the expression of miR144 in detail in normal and abnormal zebrafish blood development. The effects of miR144 overexpression and knock-down of expression will be studied in detail. To identify the targets of mir144, a multifaceted microarray analysis will be performed, and the validity of candidate targets suggested by this will then be systematically tested. When finished, these studies will have characterised the physiology of this new blood regulator and identified the way it exerts its effect.Read moreRead less
Proteome Analysis of Plant Response Pathways to Microbial Signals in the Model Legume, Medicago truncatula. This project will investigate plant responses to soil microbes in the model legume, Medicago truncatula, to provide fundamental information needed to design crops with improved abilities to interact beneficially with soil microbes. Plant development and performance are significantly influenced by soil microbes, but it is largely unknown how the information contained in microbial signalling ....Proteome Analysis of Plant Response Pathways to Microbial Signals in the Model Legume, Medicago truncatula. This project will investigate plant responses to soil microbes in the model legume, Medicago truncatula, to provide fundamental information needed to design crops with improved abilities to interact beneficially with soil microbes. Plant development and performance are significantly influenced by soil microbes, but it is largely unknown how the information contained in microbial signalling molecules is relayed to plants. Proteome analysis and immunocytochemistry will be combined to identify and localise differentially expressed proteins in roots treated with specific microbial signal molecules. Annotated Proteome databases will be generated to strengthen and complement an international project on M. truncatula genome analysis.Read moreRead less