Transcriptional Complexes In Haematopoiesis And T-cell Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins LMO2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.
Characterisation Of The Anti-apoptotic Function Of P-glycoprotein And Transcriptional Regulation Of The MDR1 Gene
Funder
National Health and Medical Research Council
Funding Amount
$324,150.00
Summary
The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a cell surface protein called P-glycoprotein (P-gp) that serves to extrude cytotoxic drugs out of the cancer cell via a pumping mechanism. Recently, we demonstrated, that in addition to its role in removing drugs from cells, P-gp can also protect cells against death induced by stimu ....The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a cell surface protein called P-glycoprotein (P-gp) that serves to extrude cytotoxic drugs out of the cancer cell via a pumping mechanism. Recently, we demonstrated, that in addition to its role in removing drugs from cells, P-gp can also protect cells against death induced by stimuli other than drugs where an efflux effect of P-gp would have no obvious benefit. This broader effect of P-gp to enhance cell survival may be explained by its ability to regulate the activity of key enzymes that exist within cells to induce cell suicide when appropriate. Some chemotherapeutic drugs activate these death enzymes (caspases) to kill target cells and it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill the cell. We are now determining how P-gp affects the activity of caspases. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated in many MDR tumor cells. It appears that the way the gene expressing P-gp (called MDR1) is packaged within chromosomes regulates gene expression levels. We are now identifying the proteins and complexes involved in regulating MDR1 expression to fully determine the molecular events that occur during the manifestation of a P-gp-expressing MDR tumor. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors in the first place.Read moreRead less
There are a number of important medical conditions that are characterised by a loss of bone. These include osteoporosis, cancer-induced bone loss, and the bone loss that causes loosening of orthopaedic prostheses. Bone loss is understood to be due to an excess of bone resorption by osteoclasts in relation to bone formation. Understanding of the regulation of osteoclast formation and activity has increased greatly in the last few years, but important questions remain. In particular, more informat ....There are a number of important medical conditions that are characterised by a loss of bone. These include osteoporosis, cancer-induced bone loss, and the bone loss that causes loosening of orthopaedic prostheses. Bone loss is understood to be due to an excess of bone resorption by osteoclasts in relation to bone formation. Understanding of the regulation of osteoclast formation and activity has increased greatly in the last few years, but important questions remain. In particular, more information is needed about the process of human osteoclast formation. We have devised a novel cell culture model of human osteoclast formation, in which osteoclast precursor cells mature into osteoclasts under the influence of human osteoblast cells. The importance of this model is that it allows us, for the first time, to investigate the role, and the potential relevance in human disease, of agents that positively and negatively affect osteoclasts. We intend also to use this model to study the way in which cancer cells in bone cause bone loss, as well as the involvement of cells of the immune system in osteoclast formation, in normal bone and in inflammatory conditions.Read moreRead less