Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study ....Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study the mechanism of hormonal control of apoptosis in order to identify components of the regulatory apparatus. Identification of precise factors that regulate PCD will not only provide basic understanding of hormone-controlled PCD, but any novel factors involved in the control of cellular levels of death activators or death inhibitors are potential targets for anticancer drug development. This proposal is based on our ongoing studies, which combine the powerful biochemical and cellular approaches with the in vivo studies in vinegar fly (Drosophila) to address complex issues that are often difficult to pursue by the direct use of mammalian systems. We believe that the results from this study will provide novel insights into the mechanisms of hormone-regulated control of PCD and how these control mechanisms are disrupted under pathological conditions.Read moreRead less
A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth ....A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth muscle. This study will examine the mechanisms that regulate ribosome synthesis. Specifically it focuses on a transcription factor termed UBF whose activity we think is critical for the regulation of the synthesis of the ribosomal RNA, the catalytic backbone of the ribosomes. Understanding the molecular mechanism(s) controlling UBF function will lead to a better comprehension of how cells modulate synthesis of functional ribosomes and how this process is deregulated during disease states associated with deregulated protein synthesis and growth such as cardiac hypertrophy and cancer.Read moreRead less
I am a developmental cell biologist and molecular geneticist focusing on mechanisms controlling cell proliferation and modelling the development of cancer in the vinegar fly, Drosophila.
Deregulation Of Ribosome Signalling, Synthesis And Function During Malignant Transformation.
Funder
National Health and Medical Research Council
Funding Amount
$522,773.00
Summary
A major feature of tumour progression is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy suggesting that it may play a causal role in cancer formation. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective in inhibiting the growth of some tumours. This study will examine the mechanisms of deregulation of ribosome biogenesis and function duri ....A major feature of tumour progression is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy suggesting that it may play a causal role in cancer formation. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective in inhibiting the growth of some tumours. This study will examine the mechanisms of deregulation of ribosome biogenesis and function during cancer formation and assess for the first time whether aberrant regulation of ribosome biogenesis and function directly contributes to the initiation and-or progression of cancer.Read moreRead less
A Lineage Specific Pathway For Progression Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$485,746.00
Summary
Melanoma is an insidious cancer, and its incidence has increased dramatically over the past four decades. Melanoma has an almost universally poor prognosis once metastasis has occurred. There are currently no treatment regimens that have a significant impact on prolonging survival or decreasing mortality from metastatic melanoma. Our preliminary data has shown the importance of a factor found in normal melanocytes in control over expression of a separate factor required for invasion and metastas ....Melanoma is an insidious cancer, and its incidence has increased dramatically over the past four decades. Melanoma has an almost universally poor prognosis once metastasis has occurred. There are currently no treatment regimens that have a significant impact on prolonging survival or decreasing mortality from metastatic melanoma. Our preliminary data has shown the importance of a factor found in normal melanocytes in control over expression of a separate factor required for invasion and metastasis of melanoma. These markers could serve as an important diagnostic marker for melanoma. Further, they may be suitable drug targets for the prevention and treatment of metastatic melanoma, and will advance our understanding of how melanoma spreads.Read moreRead less
The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via ....The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via an alternative form of the insulin receptor. We will join with our international collaborator to bring together a team of biochemists and protein structural biologists who are world leaders in understanding protein interactions in the insulin and insulin-like growth factor systems. As relatively little is known about this alternate pathway we propose to define the mechanism of binding of insulin-like growth factor-II to the alternate insulin receptor isoform. Using a combination of well-established and novel techniques we will map the interaction. This knowledge will allow design of specific inhibitors to block the action of insulin-like growth factor-II in promotion of cancer cell growth and survival without disruption of the metabolic actions of the insulin receptor.Read moreRead less
Relaxin Signalling In The Endometrium And The Regulation Of Early Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$466,125.00
Summary
Relaxin is a hormone, that is made in the ovary and the uterus, and plays a very important role in supporting the growth and development of the uterus so that the young embryo can implant properly. In fact, early pregnancy loss is associated with altered levels of relaxin in the blood. Very little is known about how relaxin works in the uterus. This project aims to address this important function, and makes use of cultured uterine cells prepared from tissues taken from women undergoing hysterect ....Relaxin is a hormone, that is made in the ovary and the uterus, and plays a very important role in supporting the growth and development of the uterus so that the young embryo can implant properly. In fact, early pregnancy loss is associated with altered levels of relaxin in the blood. Very little is known about how relaxin works in the uterus. This project aims to address this important function, and makes use of cultured uterine cells prepared from tissues taken from women undergoing hysterectomy for fibroids or similar illnesses. When these cells are grown in culture, we can mimic in vitro many of the events that occur in early pregnancy, causing the cells to differentiate and grow just as they would in vivo. Relaxin appears to exert its important effects on these cells by causing the concentration of the second messenger cAMP in the so-called stromal cells to increase greatly and in a sustained manner. It is this cAMP which is then responsible for many of the changes which are essential for healthy pregnancy. A knowledge of the molecular mechanisms behind these effects would help us firstly to understand how the uterus becomes receptive to an implanting embryo, and may explain why some women lose their babies in early pregnancy, or develop some of the negative symptoms associated with placental development such as growth restriction and preeclampsia. Relaxin appears to stimulate cells through the mediation of a new type of cell surface receptor, called LGR7. Whilst structurally this receptor looks like those for many other hormones, belonging to the group of so-called G-protein coupled receptors, it does not behave like these in natural uterine cells. Instead it appears to make use of completely new signaling pathways inside the cells. This project aims to unravel and understand these new pathways, thus providing information not only of importance for diagnosis and treatment of early pregnancy problems, but also of relevance for all other similar receptors.Read moreRead less