Molecular And Functional Characterisation Of Cell Surface Microdomains
Funder
National Health and Medical Research Council
Funding Amount
$4,803,731.00
Summary
This research program aims to gain a detailed understanding of the organisation of the cell surface at the molecular level. The cell surface is organised into domains with distinct functions. Visualisation of these domains, identifying their important components, and understanding how they form and function will have huge importance for therapeutic strategies aimed at combating the changes associated with cell transformation in cancer and in other human diseases such as muscular dystrophy.
Regulated Shuttling Of Beta-catenin And IQGAP1 Between Nucleus And Plasma Membrane In Migrating Cells
Funder
National Health and Medical Research Council
Funding Amount
$511,703.00
Summary
Inherited gene mutations that cause colon cancer kill 4,700 Australians every year. About 1 in 21 Australians develop colorectal cancer by age 75. Activation of the beta-catenin protein is a critical switch in the path to colon cancer. We discovered that beta-catenin, and another protein it interacts with called IQGAP1, move between different cellular compartments. We plan to study this process in more detail, as it relates to how beta-catenin works and to understanding its role in cancer.
Structural Basis Of Ligand Binding To Type 1 Insulin-like Growth Factor Receptor (IGF-1R)
Funder
National Health and Medical Research Council
Funding Amount
$446,562.00
Summary
Insulin-like growth factors are involved in normal growth and development. However, they are also implicated in cancer development and progression. We are seeking to understand the way in which these growth factors bind to their receptor on the surface of the cell and stimulate the cell to survive, proliferate and migrate to new tumour sites. Such knowledge will be useful in the design of molecules that could potentially intervere with this process and thus be used as anti-cancer therapeutics.
Regulation Of Signal Transduction By Cbl: Investigation Of Effects On The Cytoskeleton, Cell Adhesion And Cell Motility
Funder
National Health and Medical Research Council
Funding Amount
$256,527.00
Summary
Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation ....Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation, by detailed studies of the molecular mechanisms involved, could lead to significant advances in medical sciences. In particular, treatment of cancer and spinal injuries are likely to benefit from further development of Rho-signalling research.Read moreRead less
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
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
Inhibition Of Nef-activated Src-family Kinases By CHK
Funder
National Health and Medical Research Council
Funding Amount
$514,307.00
Summary
HIV hijacks infected blood cells to produce its own proteins. Nef is one of these proteins and Nef alone is sufficient to cause an AIDS-like disease. Recently, we discovered that a protein called CHK can inhibit Nef. Our research will determine how CHK inhibits Nef and test the feasibility of drugs based on CHK. Such drugs would slow AIDS progression, assisting conventional therapies and patients' immune systems to combat the infection, leading to longer, healthier, more productive lives.
Regulation Of The Tumour Suppressors APC And BRCA1 By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$530,874.00
Summary
Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to devel ....Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to development of colon cancer and breast cancer, respectively, contain signals that dictate their movement within the cell. Our novel preliminary findings reveal that APC and BRCA1 are able to move in and out of the cell nucleus. We aim to define how this occurs, and examine how the regulation of their cellular location affects the normal function of these cancer-suppressing proteins. Finally, abnormalities in the nuclear passage of APC or BRCA1 might explain their altered cellular location in cancer cells.Read moreRead less
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.
The regulated movement of membrane receptors and ligands between the cell surface and intracellular compartments is vital to many cellular operations, including communication between cells and their environment. However, the molecular details of these sorting events remain poorly defined. Determination of the mechanisms that control the cellular distribution of receptors is critical for understanding normal cellular processes and in pathological processes like tumorigenesis.