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
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
Regulation Of Hedgehog Signalling Through Intracellular Trafficking Events
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which ....The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which operate to ensure that this complex pathway of interacting molecules functions correctly during embryonic development. By understanding how this regulation occurs we will gain valuable insight into how disruption of this pathway results in such a range of disease, as well as into how agents which modulate this pathway may potentially act in a therapeutic setting.Read moreRead less
The Role Of Cholesterol In Patched/hedgehog Signalling During Mammalian Development.
Funder
National Health and Medical Research Council
Funding Amount
$198,660.00
Summary
Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating sign ....Fluctuations in levels of cholesterol during development of the mammalian embryo have been shown to have catastrophic affects leading to gross deformities particularly in terms of brain and facial development. The requirement of the developing embryo for cholesterol has been linked to the patched-hedgehog signalling pathway which we have previously shown to be central to mammalian development as well as tumour formation. In particular, the patched protein which is responsible for regulating signalling through this complex cascade of protein interactions has a domain similar to that which in other proteins has been shown to detect and respond to intracellular levels of cholesterol. The patched protein binds to hedgehog at the surface of the cell and mediates the transduction of the the hedgehog signal into the cell. By analogy to the role of sterol sensing domains in other proteins, we hypothesise that this domain in patched detects fluctuations in intracellular cholesterol levels which in turn alter trafficking of patched to the cell surface where it can participate in the hedgehog receptor complex. This hypothesis is supported by our preliminary data which suggests that patched is normally localised both at the cell surface and intracellularly. We are proposing a series of experiments to test our hypothesis, most of which deal with determing the localisation of patched in a cell culure system exposed to agents aimed at varying the intracellular levels of cholesterol. Subcellular localisation of patched will be analysed by immunofluorescence, electron microscopy and immunoblotting analysis. We will also test the ability of patched to aggregate at the cell surface with other molecules important in receiving and sending the hedgehog signal. The experiments in this proposal are likely to give the first clues as to the function of the sterol sensing domain in patched and its role in mediating the vital link between cholesterol and embryonic development.Read moreRead less
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 Characterisation Of SNARE Protein Complexes Involved In Insulin-regulated Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
Insulin-regulated glucose transportation is defective in type 2 diabetes, a disease that is a major health problem worldwide and in some cases can lead to death. The aim of this work is to investigate the molecular structure and function of proteins critical to the transportation and delivery of glucose to muscle and fat cells, which will lead to the validation of new therapeutic targets and the development of new treatments for diabetes.
Role Of FHA Domains As Protein-protein Interaction Modules In Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$191,973.00
Summary
The proper processing of information in cells involves the association of different proteins to signalling complexes. We will decipher the role the so-called FHA module plays in the formation of protein complexes. FHA modules are present in several proteins that are important for the repair of damaged DNA and the stability of chromosomes. Understanding the structure and function of this module will be relevant for various forms of cancer where DNA is damaged.