The Physiological and Pathophysiological Roles of Melanotransferrin

黑色素转铁蛋白（MTf）是一种膜结合分子，最初在恶性黑色素瘤、皮肤癌和其他肿瘤中发现。有趣的是，MTf与血清铁结合蛋白转铁蛋白有许多相似之处，最初认为MTf在这些细胞的铁摄取中起作用。然而，申请人的一系列研究表明，MTf在黑色素瘤细胞的铁摄取中并不起主要作用（Richardson等，1990,1991a,b）。事实上，这些细胞吸收的大部分铁都是通过转铁蛋白与转铁蛋白受体的结合。最近，在目前的NHMRC资助下，我们已经能够确认并显著扩展我们之前的研究，令人信服地表明MTf不参与黑色素瘤细胞的铁摄取，MTf在黑色素瘤细胞中表达得非常高（Richardson 2000 Eur）。生物化学学报，267（已出版）。此外，我们发现MTf在50个人体组织中的表达与众所周知参与铁运输的转铁蛋白和转铁蛋白受体（TfR）非常不同。例如，TfR在需要大量铁的组织中高水平表达。胎盘和骨髓。相比之下，MTf在这些组织中的表达水平并不高，但在诸如唾液腺等意想不到的部位中发现了大量表达。此外，MTf的表达广泛存在于各种组织中，与预期相反，在正常组织中发现的MTf表达水平高于胎儿组织。同样有趣的是，在阿尔茨海默病患者的血液和大脑中发现了MTf。我们的研究结果表明，除了铁摄取外，MTf还可能发挥其他意想不到的作用。本提案将评估MTf在细胞功能中的作用。这一信息对于理解MTf在癌细胞、阿尔茨海默病和其他组织（如脑膜）中的功能非常重要。唾液腺)，在那里它的表达水平非常高。

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.