VITAMIN K-DEPENDENT PROTEINS IN BLOOD AND DEVELOPMENT

在唯一已知的依赖于维生素K的生物过程中， 维生素K-依赖性谷氨酰羧化酶催化 谷氨酸翻译后修饰为羧基谷氨酸 在维生素K依赖蛋白的合成过程中。这 修饰对于所有已知的生物活性都是必不可少的。 维生素K依赖蛋白质。羧化酶的底物包括 几种参与血液凝固和骨基质的蛋白质 蛋白质和气体6. Gas 6是一种细胞周期调节蛋白，是一种配体， 受体酪氨酸激酶，并已牵连在预防 生长停滞细胞的凋亡。虽然我们以前专注于 我们对维生素K依赖性羧化在 止血，我们最近已经证明肝外表达 成年和胚胎大鼠维生素K依赖性羧化酶基因 组织，支持假设维生素K具有重要的 血液凝固之外的生理作用。Warfare，一种有效的 维生素K拮抗剂是一种广泛使用的抗凝剂， 抑制维生素K依赖性羧化酶的活性。华法林 也是一种致畸剂人类母体暴露于华法林期间 怀孕与胎儿的发育异常有关， 华法林胚胎病，表明关键的发育功能 羧化酶及其底物。来自我们的新数据 实验室证明了组织特异性的时间变化 维生素K依赖性羧化酶mRNA在大鼠发育过程中的表达 胚胎组织，支持维生素K依赖性 羧化是一种发育调节的翻译后 对正常胚胎发育很重要的修饰。在当前 应用，研究建议澄清维生素K的作用， 通过检查发育和组织特异性 维生素K依赖性羧化酶在大鼠胚胎中的表达。的 维生素K依赖性羧化酶基因转录的调节将 在体外进行评估，以研究调节维生素K的因素- 在发育过程中依赖蛋白质活性。动物模型 华法林胚胎病将发展，以指导未来的体内 羧化酶底物功能的研究 正常胚胎的发育。维生素K依赖性羧化 将成为其他发展中国家的典范 胎儿发育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.