A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio, Kuopio, Finland.
Essays Biochem. 2009 Nov 4;46:125-44. doi: 10.1042/bse0460009.
Cloning of genes related to polyamine metabolism has enabled the generation of genetically modified mice and rats overproducing or devoid of proteins encoded by these genes. Our first transgenic mice overexpressing ODC (ornithine decarboxylase) were generated in 1991 and, thereafter, most genes involved in polyamine metabolism have been used for overproduction of the respective proteins, either ubiquitously or in a tissue-specific fashion in transgenic animals. Phenotypic characterization of these animals has revealed a multitude of changes, many of which could not have been predicted based on the previous knowledge of the polyamine requirements and functions. Animals that overexpress the genes encoding the inducible key enzymes of biosynthesis and catabolism, ODC and SSAT (spermidine/spermine N1-acetyltransferase) respectively, appear to possess the most pleiotropic phenotypes. Mice overexpressing ODC have particularly been used as cancer research models. Transgenic mice and rats with enhanced polyamine catabolism have revealed an association of rapidly depleted polyamine pools and accelerated metabolic cycle with development of acute pancreatitis and a fatless phenotype respectively. The latter phenotype with improved glucose tolerance and insulin sensitivity is useful in uncovering the mechanisms that lead to the opposite phenotype in humans, Type 2 diabetes. Disruption of the ODC or AdoMetDC [AdoMet (S-adenosylmethionine) decarboxylase] gene is not compatible with mouse embryogenesis, whereas mice with a disrupted SSAT gene are viable and show no harmful phenotypic changes, except insulin resistance at a late age. Ultimately, the mice with genetically altered polyamine metabolism can be used to develop targeted means to treat human disease conditions that they relevantly model.
基因克隆技术使得能够生成过度表达或缺乏这些基因编码蛋白的遗传修饰的小鼠和大鼠。我们于 1991 年首次生成了过表达 ODC（鸟氨酸脱羧酶）的转基因小鼠，此后，大多数参与多胺代谢的基因已被用于以组织特异性或普遍方式在转基因动物中过度表达相应的蛋白。这些动物的表型特征揭示了许多变化，其中许多变化无法根据先前对多胺需求和功能的了解进行预测。过度表达编码生物合成和分解代谢的诱导型关键酶（ODC 和 SSAT，分别为精脒/精胺 N1-乙酰转移酶）的基因的动物似乎具有最多的多效性表型。过度表达 ODC 的小鼠特别被用作癌症研究模型。增强多胺分解代谢的转基因小鼠和大鼠揭示了多胺池迅速耗尽以及代谢周期加速与急性胰腺炎和无脂肪表型的发展之间的关联。具有改善的葡萄糖耐量和胰岛素敏感性的后一种表型可用于揭示导致人类相反表型（2 型糖尿病）的机制。ODC 或 AdoMetDC（AdoMet[S-腺苷甲硫氨酸]脱羧酶）基因的破坏与小鼠胚胎发生不兼容，而 SSAT 基因破坏的小鼠是存活的，并且除了晚年的胰岛素抵抗外，没有表现出有害的表型变化。最终，具有遗传改变的多胺代谢的小鼠可用于开发针对它们相关模型的人类疾病状况的靶向治疗方法。
