C-Kit Signalling And Cellular Responses In Haemopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$731,115.00
Summary
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biolo ....Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biology approaches to determine the role of different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the reproductive system. It is also essential for the development and function of mast cells which trigger allergic responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been developed and are beginning to be evaluated in clinical trials. Better understanding of how individual pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs. For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic reactions without affecting the growth of normal blood cells.Read moreRead less
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.
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 BRCA1 And APC Tumour Suppressor Functions By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$433,500.00
Summary
Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laborator ....Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laboratory studies two proteins, BRCA1 and APC, which are encoded by the genes most often associated with breast and colon cancer, respectively. We have made important discoveries linking the movement and location of these proteins inside the cell with their cancer-causing activity. In this project, we will continue to study how and why APC and BRCA1 move between different compartments inside cancer cells, and how this movement can sometimes signal cancer cells to die. Detailed understanding of these processes is essential for the eventual design of drug, peptide or gene therapies aimed at correcting defects in the expression or localisation of APC or BRCA1 in breast or colon cancer cells, and hopefully provide clues for that magic bullet that specifically targets and kills cancer cells.Read moreRead less
Role Of PAK1 In Colorectal Cancer Growth And Metastasis Regulated By Gastrins
Funder
National Health and Medical Research Council
Funding Amount
$460,070.00
Summary
Increased level of PAK1(a protein kinase) was associated with the progression of colorectal (large bowel) cancer (CRC). Gastrin peptides are growth factors responsible for CRC development. The objective of this project is to determine the role of PAK1 in the regulation of CRC growth and metastasis by gastrin peptides. We will use cell culture, animal models and clinical samples in the program. A successful outcome will lead to the development of new CRC therapies such as inhibitors of PAK1.
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.
Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by ....Autophagic vacuole formation in mammalian skeletal muscle; role of FOXO proteins. Loss of muscle tissue is a hallmark of many common health problems including cancer, HIV-Aids and renal failure. Recently, we identified that a family of transcription factors termed the forkhead box class-O (FOXO) winged helix transcription factors are key regulators of both anabolic (building) and catabolic (wasting) signalling pathways. This project will investigate the molecular regulation of cell integrity by FOXO proteins. Although very basic in nature, these projects will identify how FOXO proteins regulate muscle cell building and wasting and, therefore, present a potential therapeutic target for muscle wasting diseases, making this project highly significant.Read moreRead less
The function of truncated MEK1 protein in a G2 phase cell cycle delay and in mitosis. Understanding cell proliferation. Intracellular signaling pathways controlling cell growth are often mutated in cancers and other hyperproliferative diseases. Understanding precisely how these pathways operate and how mutations of these pathways can contribute to uncontrolled growth can readily provide new targets for preventative therapies or cures. We have identified a novel mechanism regulating one compone ....The function of truncated MEK1 protein in a G2 phase cell cycle delay and in mitosis. Understanding cell proliferation. Intracellular signaling pathways controlling cell growth are often mutated in cancers and other hyperproliferative diseases. Understanding precisely how these pathways operate and how mutations of these pathways can contribute to uncontrolled growth can readily provide new targets for preventative therapies or cures. We have identified a novel mechanism regulating one component of a well studied pathway, the MAPK pathway, and new functions for this component. The contribution of this novel component to mechanisms involved in regulating cell growth previously through to be controlled by the canonical MAPK pathway could change our understanding of the fundamental mechanisms controlling cell growth. Read moreRead less