The Physiological And Pathophysiological Roles Of Melanotransferrin
Funder
National Health and Medical Research Council
Funding Amount
$513,437.00
Summary
Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for DNA synthesis. However, we demonstrated that MTf did not play a major ro ....Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for DNA synthesis. However, we demonstrated that MTf did not play a major role in Fe uptake by melanoma cells (DR 1990, 1991a,b, 2000). We also showed that the tissue distribution of MTf was very different to Tf and the Tf-receptor 1 (TfR1) that are well known to be involved in Fe transport. For instance, TfR1 is highly expressed in tissues with large Fe needs (e.g., placenta), while MTf is not expressed at high levels in these tissues and is found in unexpected locations (i.e., salivary gland). In contrast to expectations, MTf was also found at higher levels in normal than foetal tissue. Also interesting was the finding that MTf is found in the serum and brain of Alzheimer's disease patients. Over the last 2 years under our current NHMRC grant on MTf we have significantly extended our knowledge on this molecule. As proposed in this grant, we generated a MTf knockout mouse. This is a very exciting model that is the best way of determining the function of MTf. Furthermore, we used recombinant MTf to show that soluble MTf that is found in the plasma is not an effective Fe donor to cells (DR EJB 2002). Our results over the last 12 years indicate that MTf may play unexpected biological roles (see DR FEBS Lett 2000). For the first time, generation of our MTf knockout mouse will provide the exciting opportunity of characterising its role(s). This will be important in understanding the function of MTf in cancer cells, Alzheimer's disease and in other tissues (eg., salivary gland and kidney) where it is expressed at high levels.Read moreRead less
The Role Of Melanoma Tumour Antigen P97 (Melanotransferrin) In Melanoma Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$563,242.00
Summary
The Role of Melanoma Tumour Antigen p97 (Melanotransferrin) in Melanoma Tumourigenesis Melanotransferrin (MTf) is a homologue of the iron transport protein, transferrin, and was one of the first well characterised melanoma tumour antigens. Our published studies have shown that MTf plays an important role in melanoma tumourigenesis in vivo. In this proposal, we will assess if it is associated with melanoma progression in patient samples and examine its role in melanoma growth and metastasis.
Melanotransferrin: A “Missing Link” And A Novel Pharmacological Target For Treatment
Funder
National Health and Medical Research Council
Funding Amount
$613,848.00
Summary
Despite >30 years of research, the precise function of the protein, melanotransferrin (MTf), is unknown. However, we have breakthrough evidence that MTf stimulates WNT signalling as a major driver in cancer progression. We will investigate this hypothesis, which will underpin new cancer therapies. Indeed, we designed a new class of drugs that target the WNT pathway via up-regulating the WNT inhibitor, NDRG1. This drug (DpC) inhibits MTf expression to block tumour cell growth and metastasis.
The Physiological And Pathophysiological Roles Of Melanotransferrin
Funder
National Health and Medical Research Council
Funding Amount
$227,485.00
Summary
Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by t ....Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by these cells was via the binding of transferrin to the transferrin receptor. More recently, under the current NHMRC grant, we have been able to confirm and signficantly extend our previous studies to convincingly show that MTf is not involved in iron uptake by melanoma cells where it is expressed at very high levels (Richardson 2000 Eur. J. Biochem. 267 (in press). In addition, we showed that the expression of MTf in 50 human tissues was very different to transferrin and the transferrin receptor (TfR) that are well known to be involved in iron transport. For example, the TfR is expressed at high levels in tissues that require large amounts of iron eg. the placenta and bone marrow. In contrast, MTf was not expressed at high levels in these tissues, but was found in large amounts in unexpected locations such as the salivary gland. Furthermore, the expression of MTf was widespread through a variety of tissues, and in contrast to expectations, was found at higher levels in normal rather than fetal tissues. It is also intesting that MTf is found in the blood and brain of Alzheimer's disease patients. Our results suggest that MTf may play other unexpected roles apart from iron uptake. The present proposal will assess the roles of MTf in cellular functioning. This information will be very important in understanding the function of MTf in cancer cells, Alzheimer's disease and also in other tissues (eg. the salivary gland) where it is expressed at very high levels.Read moreRead less
I am a pharmacologist-cell biologist-molecular biologist and chemist examining the metabolism of iron in normal and neoplastic cells and the development of iron chelators for the treatment of a wide variety of diseases eg., ?-thalassaemia, cancer and Frie
I am a pharmacologist-cell biologist-molecular biologist and chemist examining the metabolism of iron in normal and neoplastic cells and the development of iron chelators for the treatment of a variety of diseases e.g., ?-thalassaemia and cancer.