Cytoskeletal Regulation Of Adhesion Structure And Cell Movement
Funder
National Health and Medical Research Council
Funding Amount
$60,420.00
Summary
Metastatic (secondary) cancers are a frequent cause of patient mortality. Central to the development of metastasis is cell motility-movement. A key component of cell movement is the way that cells bind and release the extra-cellular matrix as they move. By understanding how the dynamics of cell interaction with the matrix are regulated, we will identify molecules that are critical to the development of metastatic cancer and thus novel targets for inhibition of metastasis.
The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly e ....The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly extending NO half-life from milliseconds to hours. This has broad implications for understanding NO activity in many processes which have major vital health implications, including tumour cell killing by macrophages and blood pressure control.Read moreRead less
The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have ....The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have broad implications for understanding the activity of NO in many processes which have major health implications, including tumour cell killing by macrophages, blood pressure etc.Read moreRead less
The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate ....The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate NO's function. We will:-
(1) Examine if NO-mediated Fe release results in GSH efflux
(2) Identify the mechanism of NO-mediated Fe efflux.
(3) Assess the effect of inducing haem oxygenase 1 on Fe metabolism
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The Dynamics of Plant Cell Division-Discovering the Mechanisms of Organelle Inheritance. This project seeks to understand molecular mechanisms responsible for organelle partitioning in dividing plant cells. Understanding these mechanisms will contribute new knowledge relevant to plant biotechnology (eg chloroplast transformation, cytoplasmic male sterility, plant development and totipotency) and thus to Australian agriculture broadly. This project will enhance Australian research capacity in the ....The Dynamics of Plant Cell Division-Discovering the Mechanisms of Organelle Inheritance. This project seeks to understand molecular mechanisms responsible for organelle partitioning in dividing plant cells. Understanding these mechanisms will contribute new knowledge relevant to plant biotechnology (eg chloroplast transformation, cytoplasmic male sterility, plant development and totipotency) and thus to Australian agriculture broadly. This project will enhance Australian research capacity in the fields of organelle inheritance and plant cytoskeletal dynamics and thus will maintain Australia's leading reputation in these fields. In addition, the project will maintain a high quality and productive research environment capable of providing excellent research training for new scientists in this field. Read moreRead less
Regulation And Function Of The Protein Tyrosine Phosphatase TCPTP In Mitosis
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphata ....The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphatases play an important role in reversible protein phosphorylation and they are essential for mitosis. This grant proposal is focused on understanding the regulation and function of protein phosphatases in mitosis. Our studies will provide novel insight into processes mediating mitosis and may lead to the development of alternative strategies for treating cancer.Read moreRead less
How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different ....How do cells regulate redox environment at the subcellular level? Most organisms live in an aerobic environment that subjects their cells to reactive oxygen species. Reactive oxygen species have been proposed to lead to ageing, and in many diseases the balance between oxidising and reducing conditions (the redox environment) is perturbed. This research will identify how different cellular structures sense and maintain this redox homeostasis, not just in the whole cell, but within the different organelles in the cell. The work will help identify which cell compartments and processes are affected in different disease states and provide a fundamental understanding of how cells coordinate their different organelles to maintain the balance between oxidising and reducing conditions.Read moreRead less
Factors involved in release of cytochrome c from mitochondria during apoptosis. Mitochondria are energy-producing organelles that activate cell death by selective release of constituents, notably cytochrome c, which participate in death-signalling cascades. I aim to probe such mitochondrial release mechanisms in intact cells, by focussing on features of translocated proteins relevant to release. Cultured mouse cells lacking cytochrome c are uniquely suited to these studies. A series of cytochrom ....Factors involved in release of cytochrome c from mitochondria during apoptosis. Mitochondria are energy-producing organelles that activate cell death by selective release of constituents, notably cytochrome c, which participate in death-signalling cascades. I aim to probe such mitochondrial release mechanisms in intact cells, by focussing on features of translocated proteins relevant to release. Cultured mouse cells lacking cytochrome c are uniquely suited to these studies. A series of cytochrome c derivatives will be engineered in elongated or aggregated forms and their release studied (including interactions with putative release machinery components) following death-signal activation. The project will elucidate a central mechanism in the cell death process, highly significant in many biological contexts.Read moreRead less
Structural elucidation and functional analysis of insulin-like growth factor binding protein-3 domains. Translating information from the human genome project into information about cell function is a major challenge in the post-genome era. The multifunctional insulin-like growth factor binding protein-3 (IGFBP-3), a member of a multigene superfamily, regulates cell growth and function through numerous signalling pathways. This project will provide structural information about IGFBP-3 as a protot ....Structural elucidation and functional analysis of insulin-like growth factor binding protein-3 domains. Translating information from the human genome project into information about cell function is a major challenge in the post-genome era. The multifunctional insulin-like growth factor binding protein-3 (IGFBP-3), a member of a multigene superfamily, regulates cell growth and function through numerous signalling pathways. This project will provide structural information about IGFBP-3 as a prototype for the superfamily, and using a combination of methodologies will unravel mechanisms of IGFBP-3 action. The project will advance understanding of IGFBP-3 and superfamily functions, and provide both benefits in international research leadership and economic and health benefits in animal and human growth and metabolism.Read moreRead less
Cracking the LIM-code: Transcription factor networks in developmental biology. Our current inability to stimulate the regeneration of nervous tissue is frustrated by a lack of detailed knowledge of the complex processes that take place at the molecular and cellular levels during development. We are determining how a group of cellular proteins that have key roles in neural development interact with each other and with DNA. With this information we are developing reagents that can be used to probe ....Cracking the LIM-code: Transcription factor networks in developmental biology. Our current inability to stimulate the regeneration of nervous tissue is frustrated by a lack of detailed knowledge of the complex processes that take place at the molecular and cellular levels during development. We are determining how a group of cellular proteins that have key roles in neural development interact with each other and with DNA. With this information we are developing reagents that can be used to probe the fundamental process of cell differentiation in the central nervous system.Read moreRead less