Mackintosh C A, Pegg A E
Department of Cellular and Molecular Physiology (H166), Room C4737, Pennsylvania State University College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033, USA.
Biochem J. 2000 Oct 15;351 Pt 2(Pt 2):439-47.
Mutant Gy male mice, which have previously been described as having disruption of the phosphate-regulating Phex gene and a spermine synthase gene [Meyer, Henley, Meyer, Morgan, McDonald, Mills and Price (1998) Genomics, 48, 289-295; Lorenz, Francis, Gempel, Böddrich, Josten, Schmahl and Schmidt (1998) Hum. Mol. Genet. 7, 541-547], as well as mutant Hyp male mice, which have disruption of the Phex gene only, were examined along with their respective normal male littermates. Biochemical analyses of extracts of brains, hearts and livers of 5-week-old mice showed that Gy males lacked any significant spermine synthase activity as well as spermine content. Organs of Gy males had a higher spermidine content. This was caused not only by the lack of conversion of spermidine into spermine, but also because of compensatory increases in the activities of other polyamine biosynthetic enzymes. Gy males were half the body weight of their normal male littermates at weaning age. Hyp males, however, were no different in size when compared with their controls. High mortality of Gy males occurs by weaning age and this mortality was shown to be largely post-natal. Embryonic fibroblasts were isolated from Gy males and their normal male littermates and were similarly shown to lack any significant spermine synthase activity as well as spermine content. The lack of spermine, however, had no significant effect on the growth of immortalized fibroblasts or of primary fibroblast cultures. Similarly, there was no difference in the time of senescence of primary fibroblast cultures from Gy males compared with cultures derived from normal male littermates. However, the lack of spermine did increase the sensitivity of immortalized fibroblasts to killing by the chloroethylating agent 1, 3-bis(2-chloroethyl)-N-nitrosourea. Therefore both the Gy male mice and derived embryonic fibroblasts provide valuable models to study the importance of spermine and spermine synthase, without the use of inhibitors which may have additional side effects.
突变型Gy雄性小鼠先前已被描述为具有磷酸盐调节Phex基因和精胺合酶基因的破坏 [迈耶、亨利、迈耶、摩根、麦克唐纳、米尔斯和普赖斯（1998年）《基因组学》，48卷，289 - 295页；洛伦茨、弗朗西斯、根佩尔、博德里希、约斯滕、施马尔和施密特（1998年）《人类分子遗传学》，7卷，541 - 547页]，以及仅具有Phex基因破坏的突变型Hyp雄性小鼠，连同它们各自正常的雄性同窝仔一起接受检查。对5周龄小鼠的脑、心脏和肝脏提取物进行的生化分析表明，Gy雄性小鼠缺乏任何显著的精胺合酶活性以及精胺含量。Gy雄性小鼠的器官具有较高的亚精胺含量。这不仅是由于亚精胺向精胺的转化缺乏，还因为其他多胺生物合成酶活性的代偿性增加。Gy雄性小鼠在断奶时体重仅为其正常雄性同窝仔的一半。然而，Hyp雄性小鼠与它们的对照相比在大小上没有差异。Gy雄性小鼠在断奶时出现高死亡率，并且这种死亡率在很大程度上显示为出生后发生。从Gy雄性小鼠及其正常雄性同窝仔中分离出胚胎成纤维细胞，同样显示缺乏任何显著的精胺合酶活性以及精胺含量。然而，精胺的缺乏对永生化成纤维细胞或原代成纤维细胞培养物的生长没有显著影响。同样，与来自正常雄性同窝仔的培养物相比，Gy雄性小鼠原代成纤维细胞培养物的衰老时间没有差异。然而，精胺的缺乏确实增加了永生化成纤维细胞对氯乙基化剂1,3 - 双（2 - 氯乙基）- N - 亚硝基脲杀伤的敏感性。因此，Gy雄性小鼠及其衍生的胚胎成纤维细胞都提供了有价值的模型，用于研究精胺和精胺合酶的重要性，而无需使用可能有额外副作用的抑制剂。
