The Physiological and Pathophysiological Roles of Melanotransferrin

黑素转铁蛋白（MTF）是一种膜结合分子，最初在恶性黑色素瘤细胞和其他肿瘤中以非常高的水平被鉴定。令我们惊讶的是，我们最近的研究表明，MTF也广泛表达在正常组织（DR EJB 2000）。MTF与铁（Fe）结合蛋白转铁蛋白（Tf）有许多相似之处，最初，MTF被认为在Fe摄取中起关键作用，而Fe摄取对DNA合成至关重要。然而，我们证明MTF在黑色素瘤细胞的铁摄取中不起主要作用（DR 1990，1991 a，B，2000）。我们还表明，MTF的组织分布是非常不同的Tf和Tf受体1（TfR1），是众所周知的参与铁的运输。例如，TfR1在具有大量Fe需求的组织中高度表达（例如，胎盘），而MTF在这些组织中不以高水平表达并且在意想不到的位置发现（即，唾液腺）。与预期相反，正常组织中的MTF水平也高于胎儿组织。同样有趣的是，在阿尔茨海默病患者的血清和大脑中发现了MTF。在过去的2年中，在我们目前的NHMRC资助下，我们大大扩展了我们对这种分子的了解。正如本研究所提出的，我们产生了一种MTF基因敲除小鼠。这是一个非常令人兴奋的模型，是确定MTF函数的最佳方法。此外，我们使用重组MTF来证明血浆中发现的可溶性MTF不是细胞的有效Fe供体（DR EJB 2002）。我们在过去12年的研究结果表明，MTF可能发挥意想不到的生物学作用（见DR FEBS Lett 2000）。第一次，我们的MTF敲除小鼠的产生将提供表征其作用的令人兴奋的机会。这对于理解MTF在癌细胞、阿尔茨海默病和其他组织（例如，唾液腺和肾脏），在那里它以高水平表达。

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.