Regulation Of BRCA1 And APC Tumour Suppressor Functions By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$433,500.00
Summary
Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laborator ....Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laboratory studies two proteins, BRCA1 and APC, which are encoded by the genes most often associated with breast and colon cancer, respectively. We have made important discoveries linking the movement and location of these proteins inside the cell with their cancer-causing activity. In this project, we will continue to study how and why APC and BRCA1 move between different compartments inside cancer cells, and how this movement can sometimes signal cancer cells to die. Detailed understanding of these processes is essential for the eventual design of drug, peptide or gene therapies aimed at correcting defects in the expression or localisation of APC or BRCA1 in breast or colon cancer cells, and hopefully provide clues for that magic bullet that specifically targets and kills cancer cells.Read moreRead less
Roles Of Ndfip1 And Ndfip2 As Adaptors For The Nedd4 Family Of Ubiquitin Ligases
Funder
National Health and Medical Research Council
Funding Amount
$656,395.00
Summary
Part of this proposal is to understand how the body controls iron uptake through one of the iron transporters (DMT1). We will also study how proteins called Ndfip1 and Ndfip2 that regulate DMT1, also control other cellular processes, such as protection against brain damage following trauma. The results from this study should ultimately contribute to the development of therapies for certain human pathologies.
Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms cont ....Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms controlling this process. We hypothesise that the local environment of a cell is critical and will involve a combination of particular extracellular matrix and growth factors as well as mechanical tension and the presence of other cell types.Read moreRead less
Factors involved in release of cytochrome c from mitochondria during apoptosis. Mitochondria are energy-producing organelles that activate cell death by selective release of constituents, notably cytochrome c, which participate in death-signalling cascades. I aim to probe such mitochondrial release mechanisms in intact cells, by focussing on features of translocated proteins relevant to release. Cultured mouse cells lacking cytochrome c are uniquely suited to these studies. A series of cytochrom ....Factors involved in release of cytochrome c from mitochondria during apoptosis. Mitochondria are energy-producing organelles that activate cell death by selective release of constituents, notably cytochrome c, which participate in death-signalling cascades. I aim to probe such mitochondrial release mechanisms in intact cells, by focussing on features of translocated proteins relevant to release. Cultured mouse cells lacking cytochrome c are uniquely suited to these studies. A series of cytochrome c derivatives will be engineered in elongated or aggregated forms and their release studied (including interactions with putative release machinery components) following death-signal activation. The project will elucidate a central mechanism in the cell death process, highly significant in many biological contexts.Read moreRead less
Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs ....Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs) in insects, other mammalian IRPs probably also exist. These may be of equal importance in regulating apoptosis, especially in tissues where DIABLO is not expressed. The main aim of the proposed study is to idenitify and characterise other IRPs in mammalian cells.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0226463
Funder
Australian Research Council
Funding Amount
$160,000.00
Summary
Fluorescence Lifetime Imaging Facility. The aim of this proposal is to establish the first fluorescence lifetime imaging facility (FLIM) in Australia. The imaging technique provided by the new facility when combined with the use of novel fluorescent protein technology will enable many different events, represented by protein-protein interactions, to be non-invasively, visualised spatially and temporally inside the living cell. The new facility will provide timely state-of -the-art infrastructu ....Fluorescence Lifetime Imaging Facility. The aim of this proposal is to establish the first fluorescence lifetime imaging facility (FLIM) in Australia. The imaging technique provided by the new facility when combined with the use of novel fluorescent protein technology will enable many different events, represented by protein-protein interactions, to be non-invasively, visualised spatially and temporally inside the living cell. The new facility will provide timely state-of -the-art infrastructure necessary for research groups to further develop and maintain their international reputations, will build stronger research collaborations between partner institutions and will attract researchers from overseas.Read moreRead less
Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasi ....Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of the damaging effects of UV radiation. A better understanding of the genetic basis of UV-sensitive skin types will greatly enhance the targeting of such skin cancer-prevention campaigns, provide an understanding of changes that occur in skin pathology, and the mechanisms of sun induced tanning.Read moreRead less
Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects withi ....Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects within the cells in culture using live cell imaging, electron microscopy and biochemical analysis. This will provide a molecular basis to explain the pigmentary characteristics of individuals allowing prediction and diagnosis of their photosensitivity with important implications for skin cancer risk.Read moreRead less
Functional characterisation of CMAP, a novel centrosome- and midbody-associated protein. Cell division is a highly regulated process involving many components to produce two daughter cells which contain an equal amount of DNA. Thus incorrect localisation and modification of specific proteins that regulate this process cause cell division errors resulting in genomic instability. We have recently identified a novel protein called CMAP that is involved in the final stages of cell division, which in ....Functional characterisation of CMAP, a novel centrosome- and midbody-associated protein. Cell division is a highly regulated process involving many components to produce two daughter cells which contain an equal amount of DNA. Thus incorrect localisation and modification of specific proteins that regulate this process cause cell division errors resulting in genomic instability. We have recently identified a novel protein called CMAP that is involved in the final stages of cell division, which involves the cleavage of the cell membrane to produce two daughter cells. Here, we aim to characterise the mechanism(s) of CMAP function and to identify and characterise CMAP binding proteins to further understand the mechanisms involved in the final stages of cell division to maintain genomic stability.Read moreRead less