VITAMIN K-DEPENDENT PROTEINS IN BLOOD AND DEVELOPMENT

这是已知的唯一依赖维生素K的生物过程， 依赖维生素K的lambda-谷氨酰羧化酶催化 谷氨酸的翻译后修饰为波长-羧基谷氨酸 在维生素K依赖的蛋白质合成过程中。这 修饰对于所有已知的生物活性都是必不可少的。 依赖维生素K的蛋白质。该羧化酶的底物包括 几种与凝血和骨基质有关的蛋白质 蛋白质和Gas6。Gas6，一种细胞周期调节蛋白，是一种 受体酪氨酸激酶，并已涉及到预防 生长受阻细胞的凋亡。虽然我们之前关注的是 我们对维生素K依赖的羧化在脑内的作用的研究 止血，我们最近展示了肝外表达的 成年和胚胎大鼠维生素K依赖的羧基酶基因 组织，支持维生素K具有重要的 凝血外的生理作用。华法林，一种有效的 维生素K拮抗剂，是一种广泛使用的抗凝剂，间接 抑制依赖维生素K的羧基酶的活性。华法林 也是一种致畸剂。人类母亲在以下期间接触华法林 怀孕与胎儿的发育异常有关， 华法林胚胎病，提示关键的发育功能 用于羧基酶及其底物。来自我们的新数据 实验室展示了组织特异性的时间变化 大鼠发育过程中维生素K依赖的羧基酶基因的表达 胚胎组织，支持维生素K依赖的假设 羧化是一种发育调节的翻译后反应 修饰对于正常胚胎发育很重要。在当前 应用，建议进行研究以阐明维生素K在 通过检查发育和组织特异性进行发育 维生素K依赖的羧基酶在大鼠胚胎中的表达这个 维生素K依赖的羧基酶基因转录的调控 体外评价，以研究调节维生素K的因素 在发育过程中依赖于蛋白质活性。一种动物模型 华法林胚胎病将被开发，以指导未来的体内研究 羧基酶底物功能检测方法的研究 正常胚胎的发育。维生素K依赖的羧化作用 将成为其他受发展管制的国家的榜样 胎儿中重要蛋白质的翻译后修饰 发展。

In what is the only known biological process dependent on vitamin K, the vitamin K-dependent lambda-glutamyl carboxylase catalyzes the posttranslational modification of glutamate to lambda-carboxyglutamate in the vitamin K-dependent proteins during their synthesis. This modification is essential for the biological activities of all known vitamin K-dependent proteins. Substrates of the carboxylase include several proteins involved in blood coagulation as well as bone matrix proteins and Gas6. Gas6, a cell cycle regulated protein is a ligand for receptor tyrosine kinases and has been implicated in the prevention of apoptosis of growth arrested cells. While we have previously focused our studies on the role of vitamin K-dependent carboxylation in hemostasis, we have recently demonstrated extrahepatic expression of the vitamin K-dependent carboxylase gene in adult and embryonic rat tissues, supporting the hypothesis that vitamin K has an important physiological role outside of blood coagulation. Warfarin, a potent vitamin K antagonist, is a widely used anticoagulant which indirectly inhibits the activity of the vitamin K-dependent carboxylase. Warfarin is also a teratogen. Human maternal exposure to warfarin during pregnancy is associated with developmental abnormalities in the fetus, the warfarin embryopathy, suggesting critical developmental functions for the carboxylase enzyme and its substrates. New data from our laboratory demonstrates temporal variations in tissue specific expression of vitamin K-dependent carboxylase mRNA in developing rat embryonic tissues, supporting the hypothesis that vitamin K-dependent carboxylation is a developmentally regulated posttranslational modification important for normal embryogenesis. In the current application, studies are proposed to clarify the role of vitamin K in development by examining the developmental and tissue specific expression of the vitamin K-dependent carboxylase in rat embryos. The regulation of vitamin K-dependent carboxylase gene transcription will be evaluated in vitro to study the factors that regulate vitamin K- dependent protein activity during development. An animal model of warfarin embryopathy will be developed, to direct future in vivo studies for testing the functions of carboxylase substrates in development of the normal embryo. Vitamin K-dependent carboxylation will serve as a model for other developmentally regulated posttranslational modifications of proteins important in fetal development.