Analysis Of The C-terminal Hypervariable Region Of Ras Proteins
Funder
National Health and Medical Research Council
Funding Amount
$419,241.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutrali ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates one major signaling pathway, is mutated in 90% of pancreatic cancers, 50% of colon cancers and 30% of acute leukaemias. This leaves Ras and the signaling pathway permanently switched on causing uncontrolled cell proliferation. The clinical impact of drugs that could neutralise Ras function in these tumours is potentially enormous. Our previous work demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras gets to and attaches to the cell membrane. Once we understand this mechanism drugs can be designed to block Ras getting to the membrane. Such drugs should neutralize the effect of Ras in tumours and control cell proliferation. In fact, our previous study has already led to the identification of the first generation of anti-Ras drugs that work on this principle.Read moreRead less
The Role Of Plasma Membrane Microdomains In Cellualar Function
Funder
National Health and Medical Research Council
Funding Amount
$4,083,868.00
Summary
The planned research program relates to novel hypotheses regarding the role of cell surface domains in organising signalling pathways at the cell surface. The proposal will involve identifying the domains and molecules involved in specific signalling pathways and dissecting the formation and function of surface structures called caveolae. The findings will have huge importance for therapeutic strategies aimed at combating the cellular changes associated with cell transformation in cancer and oth ....The planned research program relates to novel hypotheses regarding the role of cell surface domains in organising signalling pathways at the cell surface. The proposal will involve identifying the domains and molecules involved in specific signalling pathways and dissecting the formation and function of surface structures called caveolae. The findings will have huge importance for therapeutic strategies aimed at combating the cellular changes associated with cell transformation in cancer and other human diseases.Read moreRead less
Tumour cells are often characterized by defects in signaling pathways. One of the most important signaling cascades involved in the development of cancer is the EGFR-Ras-MAPK pathway. EGFR is often overexpressed in breast cancer, leading to enhanced Ras signaling (hyperactive Ras) and cell transformation. The proposed project aims to identify the molecular mechanisms that can downregulate hyperactive Ras and will make a valuable contribution to our understanding of EGFR-Ras related cancers.
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.
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
Escape From BRAF-induced Human Melanocyte Senescence In The Genesis Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$601,776.00
Summary
Melanoma is the most lethal form of skin cancer and activation of the MAPK growth pathway is a crucial step in the initiation of this cancer, but alone is insufficient, as most melanocytes with active MAPK exist in a growth arrested state. The mechanisms responsible for arresting melanocytes in the presence of active MAPK will be investigated. This project will discover why some melanocytes develop into melanomas whereas most do not.
The Role Of Plasma Membrane Microdomains In Regulating Ras-dependent Raf Activation
Funder
National Health and Medical Research Council
Funding Amount
$216,100.00
Summary
In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the ....In human cancers one or more of the signaling pathways leading from growth factor receptors at the cell surface to the nucleus where cell division is initiated are subverted. For example, a protein called Ras, that regulates a series of major signaling pathways, is mutated in 25% of all human tumours. This leaves Ras and the signaling pathways permanently switched on causing uncontrolled cell proliferation. Our previous work has demonstrated that Ras must be attached to the inner surface of the cell membrane in order to function properly. This project now seeks to understand exactly how Ras attaches to and interacts with specific sites in the plasma membrane. Its is becoming clear that different isoforms of Ras, called H-, N- and K-ras have different functions in the cell which may in turn result from their different sites of attachment to the cell membrane. This is important because by understanding the precise micro-environment in which the different Ras proteins operate and how they activate subsequent proteins in their signaling networks we will be in a good position to design drugs that selectively compromise the function of each specific Ras isoform. A highly relevant example is provided by K-ras which is mutated in 90% of all pancreatic cancers and 50% of all colon cancers. Clearly the clinical impact of a drug that could selectively neutralise K-Ras function in these tumours is potentially enormous.Read moreRead less