Identification And Characterisation Of Human Telomerase Holoenzyme Components
Funder
National Health and Medical Research Council
Funding Amount
$325,091.00
Summary
DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. I ....DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells), and therefore a need for very extensive cellular proliferation. In these tissues, an enzyme called telomerase slows down (but does not completely prevent) the rate of telomere shortening by replacing some of the DNA that is lost as a result of proliferation. Telomerase is a complex enzyme with a number of subunits. In the past few years, it has started to become clear that inherited deficiencies of some of these subunits cause diseases in which cellular proliferation starts to fail at a young age. These patients typically die of bone marrow failure. In contrast to conditions where there is telomerase deficiency, the great majority of cancers have inappropriately high levels of telomerase activity which allow cancer cells to continue dividing without limit. Telomerase is therefore regarded as a very promising target for new cancer treatments. In view of the importance of telomerase to human health, it may seem very surprising that we do not yet know all of its subunits. The reason for this is that, even in telomerase-positive cancer cells, the amount of telomerase present is vanishingly small which has made it impossible so far to obtain sufficient quantities for even the most sensitive analytical techniques. We are using very large numbers of human cells grown in a bioreactor, and have devised a highly efficient method for purifying telomerase from them. We will analyse the purified telomerase by contemporary mass spectroscopy techniques, identify all of the subunits, and characterise their contribution to telomerase function.Read moreRead less
Definition Of The Role Of Senescence In Tumour-associated Endothelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$583,081.00
Summary
'Cellular senescence' is a mechanism to stop cells growing, and it may protect against tumour growth. However, it may also induce changes in cells leading to 'pro-tumour' effects. We have identified a gene - which we have called SEN1 - which induces senescence in the blood vessels of tumours. This gene may cause alterations in the blood supply to the tumour allowing it to grow and to resist chemotherapy. Understanding this gene may allow us to treat cancer by shutting off its blood supply.
Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone ....Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone can act in an apparently contradictory fashion. Its production by the embryo allows it to act back on the embryo to stimulate embryo growth and survival. The embryo (of some species) then releases other hormones which prevents the PAF from acting on the uterus. If this repression of the uterine response to PAF does not occur then PAF acts on the uterus to stop further progression of the pregnancy (luteolysis). Hormones act on cells via special cell proteins known as receptors. It seems that the receptor for PAF in the embryo and the uterus are different and may therefore result in triggering different cellular responses by these 2 tissues. We have available to us mice with mutations that stop the functioning of these two likely classes of receptors. The progress of pregnancy and the development of embryos in mice with these mutations will be studied as a means of defining how PAF acts in pregnancy. The embryo will be studied in detail to determine the nature of the changes induced within the embryo by PAF acting via its receptor. One of these receptors is an entirely new class of molecules not previously understood to be able to act as a cell signalling devise. This study will describe if and how this potential new receptor acts in the embryo, allowing future detailed investigation of its role in normal cell function. It will show how this single hormone can regulate both the uterus and embryo to have contradictory roles in the establishment of pregnancy.Read moreRead less
Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.
Heterogeneous Nuclear Ribonucleoprotein Role In Alternative RNA Splicing And Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes of DNA is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has ....Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes of DNA is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become apparent that there are many post-transcriptional events that govern how efficiently the genetic information is ultimately converted to protein molecules. An important step is the cutting out of parts (introns) of the RNA molecule that is copied from DNA, and splicing of the retained sections (exons). During this process the RNA may also lose one or more of its exons. As a result of this variable retention of exons a single gene may produce many isoforms of the protein it encodes. By this mechanism the roughly 30,000 genes in the human genome can give rise to potentially hundreds of thousands of proteins. RNA splicing connects to cancer in two ways. First, changes in the concentrations of the proteins that control splicing may change the isoforms, resulting in changes that lead to uncontrolled cell proliferation. Secondly, DNA mutations that affect the splicing process can also vary the ratios of the isoforms produced from a gene: if this occurs in a protein that is involved in the growth of cells this too may lead to cancer. In this project we will study the molecular mechanism of this alternative splicing, and particularly a group of proteins that generally favour the excision of some exons, with a focus on cancer cells. Recent publications have highlighted the potential for the therapeutic use of drugs that target the splicing apparatus: it is anticipated that studies of alternative splicing will underpin development of new therapeutic agents.Read moreRead less
Defining Stromal-Cancer Cell Interactions For Xenografting Human Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$559,635.00
Summary
Prostate Cancer research continues to be hindered by a lack of laboratory models to understand disease progression and design new drugs to cure the disease. In this study, we propose to use a new and reliable method of growing human prostate cancer tissue in mice. Using this model, we will investigate the role of hormone signalling and cellular communication in prostate cancer that may lead to new therapies for men diagnosed with organ-confined disease.
Regulation Of B Lymphocyte Survival And Tumourigenesis By The TRAF2-TRAF3-cIAP Signaling Complex
Funder
National Health and Medical Research Council
Funding Amount
$439,395.00
Summary
A major contributing factor in the development of cancer is the loss of the normal controls that regulate cell survival. We have identified a group of proteins that control the survival of B cells, the white blood cells responsible for producing the antibodies that fight infections. In this project we will investigate the mechanisms by which these proteins function and how inactivation of their functions can lead to multiple myeloma, an aggressive cancer of antibody producing cells.