Characterisation Of A New Family Of Proteins Involved In Cell Signalling, RNA Metabolism And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of th ....We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals, such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same broad group of proteins are responsible for a host of disease states in mammals including mental retardation, myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated that implicates these proteins to human dysfunction surprisingly few of these RNA-binding proteins have been identified. We have shown that the novel protein discovered in our laboratory is perturbed in cancer and we are interested in characterising its putative role in cancer. The results established in our laboratory so far would indicate that generally, G3BP-2 is expressed in normal tissue and it expression changes in some cancers studied so far. Considering that G3BP-2 lies in a pathway known to be involved in cancer progression it is important to understand what effects the inappropriate expression of G3BP-2 may have on cancer progression and survival. This project is designed to characterise what signals the cell uses to control these proteins and in turn which genes these may effect. In this way we may be able to determine how external signals may effect tumour progression and on what genes this influence is expressed. It would be hoped that this project would increase our understanding of cancer and potentially lead to new diagnostic reagents and therapies in the treatment of cancer.Read moreRead less
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
Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how thi ....Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how this differs from the conventional nuclear import pathways used by normal cellular proteins. We already have evidence that nuclear import of HIV-Tat is regulated in novel fashion by cellular factors, and intend, through determining its mechanistic basis, to be able to form the basis of a strategy to block this import pathway specifically, and thereby inhibit HIV replication. This may form the basis in the future of a new pharmaceutical approach to combat HIV-AIDS.Read moreRead less
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