Recent evidence suggests that the Siah proteins are involved in sensing low oxygen levels in cells, and subsequently activating processes to help the cell survive under these conditions. Low oxygen conditions occur in cancer and sites of inflammation, suggesting that inhibiting Siah may improve patient outcomes in diseases such as cancer and arthritis. We aim to perform a high throughput screen for drugs that inhibit Siah protein function and to test these in cancer cells.
Structural Studies Of The Jak And Abl Kinases: A Prerequisite For Drug Design
Funder
National Health and Medical Research Council
Funding Amount
$360,965.00
Summary
Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio ....Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in diseases such as cancer and immune related disorders. This fellowship aims to develop more potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled with the X-ray crystallography expertise within Monash University. This innovative approach will permit a rational structure-based drug discovery platform to be established and will lead to the creation of a portfolio of phase I therapeutics, which will be of substantial benefit in the medical health area.Read moreRead less
Prof Parton is a cell biologist studying how the plasma membrane functions in health and in disease. These studies have provided new insights into potential vehicles that can be used to introduce therapeutic agents into cells.
Functional Characterisation Of N4WBP5 And N4WBP5A, Novel Nedd4-interacting Proteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
The proteins that make up a cell must be correctly localised in order to perform their normal function. Specialised cellular activities are carried out in distinct compartments within a cell and proteins must correctly localise in them and traffic between them. Intracellular protein trafficking is a highly regulated process involving many components. Recent findings have shown that intracellular trafficking is regulated in many cases by distinct protein modifications. One such modification is ta ....The proteins that make up a cell must be correctly localised in order to perform their normal function. Specialised cellular activities are carried out in distinct compartments within a cell and proteins must correctly localise in them and traffic between them. Intracellular protein trafficking is a highly regulated process involving many components. Recent findings have shown that intracellular trafficking is regulated in many cases by distinct protein modifications. One such modification is tagging of a small protein called ubiquitin to proteins that are being trafficked. A focus of research in our laboratory is the study of a protein, called Nedd4, which directly tags proteins with ubiquitin. We have recently identified two novel proteins that interact with Nedd4 and localise to distinct subcellular compartments that are sites for the correct sorting and delivery of proteins trafficking within the cell. The main aim of our proposal is to characterise how these proteins function. We propose that these proteins are involved in intracellular trafficking and that they may function by targeting Nedd4 to the cellular trafficking machinery. This may be required for Nedd4 to tag molecules with ubiquitin that are involved in intracellular trafficking. Our experiments will test the functional relationship between Nedd4 and the novel proteins and determine the particular trafficking pathways in which these proteins are involved. Defects in cellular processes regulated by Nedd4 and other similar proteins cause a number of human diseases including an inherited form of hypertension and a specific group of cancers. In addition, a large number of human diseases result directly from defects which disrupt intracellular trafficking pathways. The results of this study will provide further insight into this essential cellular process and may ultimately contribute to the development of therapies for diseases resulting from defects in intracellular trafficking.Read moreRead less
SPRY Domain-containing SOCS Box (SSB) Protein Interaction With Par-4: Structure And Biochemical Implications
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a centra ....The suppressor of cytokine signalling (SOCS) proteins, are intracellular molecules that negatively regulate hormone and growth factor action, and whose functional importance has been borne out in many physiological studies. The SOCS box is a small part of the SOCS proteins that is believed to facilitate degradation of SOCS target proteins. The SPRY domain-containing SOCS box protein-2 (SSB-2) is one of four proteins within the greater SOCS family (SSB-1 to -4), which have a SOCS box and a central SPRY domain. The SPRY domain mediates interaction with other proteins within the cell. Over 300 proteins are known to contain a SPRY domain. We recently determined the first atomic structure of a SPRY domain as part of SSB-2, using nuclear magnetic resonance (NMR) spectroscopy. We further identified Par-4 (prostate apoptosis response-4) as a novel and direct protein binding partner for SSB-1, -2 and -4, but not SSB-3. Extensive mutational analysis subsequently identified a series of SSB-2 mutants that were unable to bind Par-4 but retained structural integrity. Cancer cells develop through a series of genetic events and escape programmed cell death or apoptosis, continuing to grow inappropriately. Par-4 was originally discovered as a gene up-regulated in prostate cancer cells undergoing apoptosis and primarily appears to sensitise cancer cells to apoptotic stimuli. This proposal aims to further investigate SSB-Par-4 binding. The 3D structure of the complex will be determined and biochemical consequences of this interaction characterised. If SSB proteins regulate Par-4 levels, then chemical disruption of SSB-Par-4 binding could potentially result in an increase in Par-4 protein levels, making cancer cells more susceptible to killing by cytotoxic drugs.Read moreRead less
Mechanisms Of Control Of Cell Growth And Proliferation By The AKT Kinase Family
Funder
National Health and Medical Research Council
Funding Amount
$568,452.00
Summary
Ribosome synthesis and function is critical for normal cell growth and division and hence this process is exquisitely regulated. Conversely, de-regulated cell growth can lead to cancer. We have identified new roles for the AKT and SGK families of kinases in controlling this process. This proposal aims to establish the mechanisms by which these enzymes control ribosome synthesis to better understand growth control and to provide insight for targeting these pathways in growth driven cancers.
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less
Use Of Novel Transfection Protocols To Study Protein Trafficking In Malaria-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythroc ....Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythrocytes of its human host. The parasite transports proteins to the erythrocyte membrane so as to modify the properties of its adopted cellular residence. The parasite proteins that are deposited at or in the erythrocyte membrane increase the leakiness and the stickiness of the parasitised erythrocytes. This allows more efficient uptake of nutrients and allows the parasitised erythrocytes to adhere to blood vessel walls, thereby avoiding passage through the spleen. Adherence of parasitised erythrocytes to capillaries in the brain is thought to lead to the development of the complication known as cerebral malaria. This complication is responsible for most of the deaths due to malaria. In order to traffic the adherence proteins to the erythrocyte surface, the parasite establishes a novel transport pathway for moving proteins across the erythrocyte cytoplasm. As the uninfected erythrocyte has no means, nor requirement, for moving proteins, this novel transport mechanism may represent a target for drugs that kill the malaria parasite without being toxic to humans. The pathways for the movement of proteins around the infected erythrocyte are largely unknown. We propose to use techniques to introduce foreign genes into malaria-infected erythrocytes to unravel the details of the molecular machinery and the ticketing system that the parasite uses to traffic proteins to their correct destinations in its adopted home.Read moreRead less