A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
Ras Signalling And Cholesterol Efflux From Late Endosomes
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
Accumulation of cholesterol is a hallmark of early atherosclerotic lesions, known as foam cell formation. Hence the stimulation of cholesterol removal (efflux) from macrophages has great therapeutic potential. High Density Lipoproteins (HDL) and apolipoprotein A-I (apoA-I) stimulate efflux via activation of HDL-apoA-I receptors and poorly understood signalling pathways. This application is investigating the role of the Ras-MAPK signalling pathway in promoting efflux from late endosomes.
Targeting Of The APC Tumour Suppressor To Mitochondria: Implications For APC Regulation And Cellular Function
Funder
National Health and Medical Research Council
Funding Amount
$390,116.00
Summary
Inherited mutations in the APC gene cause colon cancer, and kills 4,700 Australians every year. About 1 in 21 Australians develop colorectal cancer by the age of 75. APC mutations change cells in different ways, triggering the cancer process. We have discovered a new pathway, involving altered movement of APC to mitochondria in tumour cells. This study will investigate how this cancerous change may help our understanding of colon cancer progression.
Regulation Of PtdIns(3,4,5)P3 By Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5- ....Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5-phosphatases. We propose the 5-phosphatases are essential for normal cell growth. Several studies have suggested in their absence tumour formation may occurr. We have identified a new member of this enzyme family called SHIP-2. This proposal aims to investigate the mechanisms by which this enzyme family metabolises signalling molecules and thereby regulates cell growth. We will also characterize how the 5-phosphatases control the normal pathways by which primitive cells differeniate into mature cells.Read moreRead less
The Interaction Between CD46 And PSD-95/Dlg-4: Roles In Cell Polarisation And CD46 Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$70,000.00
Summary
Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single ....Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single protrusion, or uropod, that forms the basis for cell-cell interactions, (ii) the formation of an immune synapse which allows a T cell to recognise a pathogen, and (iii) the direction of the cellular killing machinery towards the target. The process of cell polarisation is best characterised in neurons and epithelial cells, both of which are asymmetric. In each cell type, a major mechanism of regulating polarisation is the expression and targeting of a family of proteins containing regions called PDZ domains. PDZ domains mediate protein-protein interactions and so allow the assembly of large molecular scaffolds which hold proteins in specific cell sites. The loss of cell polarity in some cells is thought to cause uncontrolled proliferation and tumour progression, and some of the PDZ-containing proteins are tumour suppressors. We have identified a PDZ-containing protein that is polarised in T cells, and have evidence that this protein interacts with and controls the polarisation of a cell surface receptor whose functions include the regulation of T cell function and proliferation. The aim of this proposal is to determine the mechanisms and functional consequences of polarisation of these two proteins in T cells, and to determine whether their interaction or polarisation is important for T cell proliferation.Read moreRead less
Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single ....Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single protrusion, or uropod, that forms the basis for cell-cell interactions, (ii) the formation of an immune synapse which allows a T cell to recognise a pathogen, and (iii) the direction of the cellular killing machinery towards the target. The process of cell polarisation is best characterised in neurons and epithelial cells, both of which are asymmetric. In each cell type, a major mechanism of regulating polarisation is the expression and targeting of a family of proteins containing regions called PDZ domains. PDZ domains mediate protein-protein interactions and so allow the assembly of large molecular scaffolds which hold proteins in specific cell sites. The loss of cell polarity in some cells is thought to cause uncontrolled proliferation and tumour progression, and some of the PDZ-containing proteins are tumour suppressors. We have identified a PDZ-containing protein that is polarised in T cells, and have evidence that this protein interacts with and controls the polarisation of a cell surface receptor whose functions include the regulation of T cell function and proliferation. The aim of this proposal is to determine the mechanisms and functional consequences of polarisation of these two proteins in T cells, and to determine whether their interaction or polarisation is important for T cell proliferation.Read moreRead less
The Structural Basis Of Cytokine Signalling Inhibition
Funder
National Health and Medical Research Council
Funding Amount
$239,473.00
Summary
Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to ....Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to these protein messengers however it is just as vital that they don't overreact. Many human diseases, especially inflammatory diseases such as rheumatoid arthritis and type II diabetes, are due to aberrant cytokine signaling. To ensure this doesn't occur, cells have evolved a mechanism to quickly switch off the signaling cascade after it has started. This mechanism involves an entire family of proteins, the Suppressors of Cytokine Signalling (SOCS) family. These proteins can act via two distinct mechanisms. The first is to directly block the JAK-STAT proteins, proteins that initiate the intracellular part of the signaling cascade. The second mechanism has been less well studied, it involves the SOCS proteins upregulating the degradation of signaling intermediates. The SOCS proteins can do this through the action of a 40 residue domain called the SOCS box. The SOCS box directs proteins bound to other domains of the SOCS proteins to be degraded by interacting with a complex called an E3 ubiquitin ligase. This project involves determining the three-dimensional atomic structure of the SOCS-E3 ligase interaction and investigating biophysical aspects of the interaction. This information will lead to a fuller understanding of the mechanism of signaling inhibition and will provide information crucial to the design of SOCS inhibitors. Such inhibitors would be therapeutically important in the treatment of a number of human diseases such as cancer, arthritis and type II diabetes.Read moreRead less
The Role Of Cholesterol In Patched/hedgehog Signalling During Mammalian Development.
Funder
National Health and Medical Research Council
Funding Amount
$198,660.00
Summary
Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating sign ....Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating signalling through this complex cascade of protein interactions has a domain similar to that which in other proteins has been shown to detect and respond to intracellular levels of cholesterol. The patched protein binds to hedgehog at the surface of the cell and mediates the transduction of the the hedgehog signal into the cell. By analogy to the role of sterol sensing domains in other proteins, we hypothesise that this domain in patched detects fluctuations in intracellular cholesterol levels which in turn alter trafficking of patched to the cell surface where it can participate in the hedgehog receptor complex. This hypothesis is supported by our preliminary data which suggests that patched is normally localised both at the cell surface and intracellularly. We are proposing a series of experiments to test our hypothesis, most of which deal with determing the localisation of patched in a cell culure system exposed to agents aimed at varying the intracellular levels of cholesterol. Subcellular localisation of patched will be analysed by immunofluorescence, electron microscopy and immunoblotting analysis. We will also test the ability of patched to aggregate at the cell surface with other molecules important in receiving and sending the hedgehog signal. The experiments in this proposal are likely to give the first clues as to the function of the sterol sensing domain in patched and its role in mediating the vital link between cholesterol and embryonic development.Read moreRead less