The Regulation Of PI 3-kinase Second Messenger Molecules, PtdIns(3,4)P2 And PtdIns 3-P.
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been describ ....Cells respond to the external environment, hormones, and growth factors by generating messages inside the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases. There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in many human cancers. Inherited cancer syndromes have been described that have lost the ability to switch off PI 3-kinase signals. The current project aims to investigate a recently identified enzyme called the 4-phosphatase that has the ability to terminate PI 3-kinase signals. Recent studies have shown this enzyme regulates cell growth. In addition key experiments have shown the enzyme is important as it may regulate certain strains of bacterial infection. This research proposal aims to investigate how the enzyme works to regulate these growth promoting signals. This may help us develop novel therapeutic strategies to control cell growth.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.
FHA Domain-dependent Functions Of Cell Cycle Checkpoint Kinases
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss ....Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss of vast tracts of DNA or inappropriate genome rearrangements, that may ultimately give rise to cancer. To prevent such dire consequences, all organisms from yeast to man contain molecular checkpoints that sense the presence of DNA damage and then activate a cellular response program that includes damage repair and prevention of cell division while damage persists. These molecular checkpoints are highly conserved throughout evolution which allows us to analyse the details involved in simple organisms such as yeast, to draw general conclusions on their function in more complex human cells. Along these lines, we are studying the function of two yeast proteins that are similar to the human Chk2 protein, a tumour suppressor that is mutated in a subset of families suffering from the Li-Fraumeni multi-cancer syndrome. We have identified new pathways by which these proteins contribute to the survival of cells after treatment with DNA damaging agents and will further charaterise these in the present proposal.Read moreRead less
Structural Characterisation Of Phosphopeptide Recognition By FHA Domains
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signa ....Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signalling protein partners. Many proteins containing FHA modules are important for the repair of damaged DNA and the stability of chromosomes. The aim of our studies is to understand the molecular and atomic details of how FHA modules bind their partners. This is the first step towards designing therapeutic agents against various forms of cancer where DNA is damaged.Read moreRead less