Afri 1: Gene Cloning and its Role in Liver Regulation

生物医学研究的一个基本目标是了解在发育和疾病过程中调节基因表达的过程。小鼠甲胎蛋白三磷酸腺苷特别适合于此。甲胎蛋白在胎儿肝脏中高水平表达，但在成人肝脏中不表达。这是由于围产期转录减少了10,000。在成人肝脏中，AFP基因可以在损伤后重新激活，在肝细胞癌中也可以。甲胎蛋白调控的这些方面--肝发生时的甲胎蛋白激活，出生时的抑制，以及肝癌和再生中的重新激活--引起了人们对该基因控制的浓厚兴趣。甲胎蛋白抑制基因在一定程度上受甲胎蛋白调节基因1(Afr1)的调节。Afr1最初是通过不同品系小鼠AFP水平的差异来鉴定的。因此，与大多数控制基因表达的哺乳动物因子不同，Afr1是从基因上发现的。特别有趣的是，Afr1似乎通过一种将转录与转录后事件偶联的机制来调节AFP。虽然文献中已经建立了这些事件之间的联系，但调节这些联系的机制才刚刚开始被发现。利用现代分子遗传学的工具，我们提出了通过定位克隆来鉴定Afr1基因。然后，我们可以了解Afr1是如何调控AFP的，我们可能会更多地了解转录/转录后/转录联系，以及这可能是如何在发育过程中调节以控制基因表达的。

A fundamental goal of biomedical research is to understand the processes that regulate gene expression during development and disease. The mouse alpha-fetoprotein ATP is particularly well suited for this. AFP is expressed at high levels in the fetal liver but is off in the adult liver. This is due to a 10,000 reduction in transcription during the perinatal period. The AFP gene can be reactivated in the adult liver in response to injury and in hepatocellular carcinomas. These aspects of AFP regulation-AFP activation during hepatogenesis, repression at birth, and reactivation in liver cancer and regeneration-have led to considerable interest in the control of this gene. Postnatal AFP repression is regulated in part, by a locus called Alpha-fetoprotein regulator 1 (Afr1). Afr1 was originally identified by differences in AFP levels in different mouse strains. Thus, unlike a majority of mammalian factors controlling gene expression that have been identified using biochemical approaches, Afr1 was revealed genetically. Of particular interest, Afr1 appears to regulate AFP by a mechanism that couples transcription to post-transcription events. While a connection between these events has been established in the literature, mechanisms that exist to modulate these connections are only beginning to be uncovered. Using tools of contemporary molecular genetics, we propose to identify the Afr1 gene by positional cloning. We can then understand how Afr1 regulates AFP and we are likely to learn more about the transcription/post/transcriptional connections as well as how this may be developmentally regulated to control gene expression.