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。小鼠的甲胎蛋白ATP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。这是由于在围产期转录减少了10,000。AFP基因可以在成人肝脏损伤和肝细胞癌中被重新激活。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、肝癌和再生时的甲胎蛋白再激活——引起了人们对该基因控制的极大兴趣。出生后AFP的抑制在一定程度上是由一个叫做α胎蛋白调节因子1 （Afr1）的基因座调节的。Afr1最初是通过不同小鼠品系中AFP水平的差异来鉴定的。因此，与大多数使用生化方法确定的控制基因表达的哺乳动物因素不同，Afr1是遗传上揭示的。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。虽然这些事件之间的联系已经在文献中建立起来，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，我们提出了定位克隆鉴定Afr1基因。我们可以了解Afr1如何调节AFP，我们可能会了解更多关于转录/后/转录连接以及如何通过发育调节来控制基因表达的信息。

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.