Loss Of Cytostatic Regulation By TGF-beta During EGFR-driven Tumor Development
Funder
National Health and Medical Research Council
Funding Amount
$605,031.00
Summary
Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulato ....Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulators in tumour formation and as such they are potential therapeutic targets. However, while both pathways have been studied extensively, little is known about the cross-talk between the TGF-b and EGF pathways. This project will establish the generality of a new tumor signaling axis, namely EGFR-Stat3-Smad7-TGF-b in EGFR-overexpressing tumors. Practically, it will provide guidelines for the development of new approaches for treating effectively the EGFR-driven tumors.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
Characterization Of HLS5, A Novel Tumor Suppressor Gene
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 ....HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 is a tumour suppressor gene comes from the proteins it associates with these partner molecules are involved in DNA repair or DNA regulation. When we introduced HLS5 into cancer cells, it slowed their growth and reduced their ability to form tumours. The aim of this project therefore, is to undertake a detailed analyses of the HLS5 gene and to determine the function of its protein product. A combination of approaches will be used in this study. We will: (i) alter the amount of HLS5 expression in cancer cells, (ii) characterize the proteins which bind to HLS5, (iii) determining where HLS5 localizes in the cell, (iv) analyze mice with lack the gene for HLS5, (v) assess the involvement of HLS5 in a human leukemia (vi) analyze HLS5 messenger RNA which produces the protein, and (vii) determining the structure of HLS5 protein. These studies should provide valuable information on how HLS5 functions, as well as its role in cancer formation.Read moreRead less
Apoptosis is a fundamental mechanism in regulating normal development and preventing cancer. Cancer cells must avoid apoptosis and also adapt to harsh metabolic environments in order to survive in the absence of effective nutrient supply and to resist the action of certain drugs. This project will provide a detailed analysis of metabolic changes allowing cells to survive long periods when the apoptotic process is absent and nutrients are limiting.
Specificity Of Smad Proteins In Transforming Growth Factor-beta Signaling
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colo ....Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colorectal and pancreatic cancers. The Smad proteins (there are ten of them) are critical components of TGF-beta cellular actions. In fact, Smad4 also called DPC4 for deleted in pancreatic carcinoma locus 4. This project addresses how each Smad protein works at molecular level in the cell, and which part of biological functions it regulates. Collectively, the outcomes of the project may provide clear and specific molecular targets to treat TGF-beta related diseases such as colorectal and pancreatic cancers.Read moreRead less
The Role Of The 72 KDa Inositol Polyphosphate 5-phosphatase In Cellular Function.
Funder
National Health and Medical Research Council
Funding Amount
$549,196.00
Summary
Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of t ....Cells respond to external signals and the environment to undergo cell growth, secretion and-or other specialized functions including control of cell death and-or cell size. We have identified a new enzyme (72kDa 5-phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase. Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in breast and ovarian cancer. We aim to determine the specific role each of these PI3-kinase signals plays in the activation of the oncogene. In addition the levels of the 72kDa enzyme is altered in some cervical and lymphoma cancers. We will image live cells containing specific fluorescent probes under different conditions and study the activation and location of these probes in order to understand how different PI3-kinase signals are regulated in time and space. In addition to regulating signals that are involved in cancer, PI3-kinase controls signals that are important for proper immune function. Phagocytosis is a biological process where specialised immune cells (macrophages) take up and remove harmful particles such as bacteria or tumour cells from the circulation. This process depends on PI3-kinase and the signals it produces. We will determine whether the 72 kDa enzyme, which is expressed in macrophages, plays a role in regulating these signals during phagocytosis. We have shown that the 72 kDa enzyme can interact with several different proteins which may affect its location and activity within the cell. We will examine the effect of these interactions on the PI3-kinase signals which are involved in cell survival and immune responses. We will study the function of the enzyme in the intact animal by producing mice which lack this enzyme. Given the possible role of this enzyme in cancer, these mice will be examined for their susceptibility to develop tumours.Read moreRead less
The Role Of Mal In Toll-like Receptor Signal Transduction Of The Pro-inflammatory Response.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune syste ....Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune system. Dysregulation of the pro-inflammatory response can lead to sepsis. Recently, the mammalian receptor for LPS was found to be Toll-like receptor (TLR)-4, the activation of which activates a signal transduction pathway that initiates the pro-inflammatory response. We have previously shown a key role for an adapter protein called Mal in mediating signal transduction pathways upon activation of TLR-4. Interaction of Mal with a key signal transduction mediator called TRAF6 has been shown to induce the activation of the pro-inflammatory response. Furthermore, Mal has been found to undergo degradation which may indicate a means of regulating the continued activation of the pro-inflammatory pathway. This research program will investigate the role of Mal in mediating signal transduction in TLR activated macrophages, key responsive cells of the innate immune system to microbial infection. A greater understanding of these processes will assist in the development of therapeutics to alleviate the consequences of microbial-induced inflammation, including chronic inflammatory diseases and sepsis.Read moreRead less