Post Transcriptional Regulation Of The Plasminogen Activator Inhibitor Type 2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its activ ....The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA). Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors. This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to influence PAI-2 levels in the body.Read moreRead less
Regulation Of Tissue-type Plasminogen Activator Gene Expression In Endothelial Cells And In Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$244,009.00
Summary
Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how t ....Tissue-type plasminogen activator (t-PA) is an enzyme which plays an important role in the removal of blood clots from the circulation. One of the major sites of production of t-PA are endothelial cells which line the blood vessel wall. The rate of t-PA production is greatly influenced by factors released from other cells. One of these factors is tumour necrosis factor (TNF). The t-PA gene is switched off in endothelial cells exposed to TNF. One of the aims of this project is to understand how the t-PA gene is suppressed by TNF in human endothelial cells and in transgenic mice. The transgenic mice we have available express the regulatory region of the t-PA gene (called the gene promoter) connected to a reporter gene called LacZ. We will use these animals to visualise the expression pattern of LacZ expression under normal conditions and in mice treated with TNF. The results of these experiments will provide new information as to how the t-PA gene is controlled in cells and in the body.Read moreRead less
Regulation Of Adult Colonic Crypt Homeostasis And Activation Of Colon Cancer Metastasis Genes By C-Myb
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number ....Regulation of normal colon biology and activation of genes involved colon cancer The c-myb gene is essential for the normal biology of the blood system and the colon. This gene is involved in regulating the balance between the production of new cells and their timely removal once they have completed their assigned tasks. There is a large body of evidence that supports the role of c-myb in the regulation of the blood system. We believe that the rules that govern the production of the huge number of cells needed to have a healthy blood system are similar if not identical to the rules used by the colon. This is because the colon also produces a massive number of cells each with special tasks and a defined life span of a few days. It is this rapid expansion of cell numbers and the programmed short life span of cells that necessitates multiple controls and very tight regulation. Furthermore if this process is hijacked by genetic changes that undermine these controls then there are numerous opportunities to initiate and potentiate malignant change or cancer. This project examines the role of the same genes in two contexts. Firstly when the genes are expressed at normal, highly regulated levels associated with the normal biology of the colon. The second context is when these genes are permitted to be over-expressed and thus drive processes for longer or in inappropriate situations leading to malignant growth.Read moreRead less