Construction and analysis of a model mouse with cancer caused by oxidative stress.

细胞色素B大亚基（Cytochrome b large subunit，CYT-1，SDHC）是电子传递系统中复合物II的一个亚基，突变后，O_2 ~-产生增加，导致能量代谢异常，导致细胞凋亡。最近，具有血管化头颈部肿瘤遗传倾向的个体（即，副神经节瘤）已被证明含有复合物II中的几种突变之一。为了进一步探讨线粒体氧化应激在肿瘤发生中的作用，我们建立了SDHC基因点突变的转基因细胞系和小鼠，发现该细胞系中存在大量凋亡细胞，部分逃避凋亡的细胞发生转化。来自线粒体的氧化应激导致病理学，例如导致早熟衰老的细胞凋亡以及导致肿瘤发生的转化。细胞凋亡是通过激活线粒体信号转导途径诱导的。凋亡的诱导可以增强细胞生长能力受抑制的老化细胞中存活细胞数量的减少，另一方面，可以在具有过氧化应激的转化细胞中具有生长抑制的效果。为了在哺乳动物个体水平上验证氧化应激与肿瘤发生的关系，我们构建了具有Tet-on/off系统的SDHC条件转基因小鼠。四环素对转基因的诱导作用在除脑和肌肉外的其他器官和组织中均有表达。由于对氧化应激高度敏感，转基因小鼠有望成为氧化应激导致癌症的模型小鼠。

A mutation in a subunit, cytochrome b large subunit (C.elegans : CYT-1 ; mouse and human : SDHC), of complex II in electron transport system, results in increasing O_2^- production and therefore lead to abnormal energy metabolism and apoptosis. Recently, individuals with an inherited propensity for vascularized head and neck tumors (i.e., paragangliomas) have been demonstrated to contain one of several mutations in complex II. To further explore the role of oxidative stress from mitochondria on cancer, we established transgenic cell line and mouse with a point mutation in the SDHC gene.There were many apoptotic cells in this cell line, and some cells that escaped from apoptosis underwent transformation. Oxidative stress from mitochondria leads to pathology such as apoptosis resulting precocious aging and also transformation resulting tumorigenesis. The supernumerary apoptosis was induced by activation of a signal transduction pathway via mitochondria. The induction of the apoptosis may enhance the reduction of a number of survived cells in aged cells suppressed cell growth ability and, on the other hand, may have an effect of growth suppression in transformed cells having hyper-oxidative stress. It is suggested that oxidative stress is deeply related with benign tumorigenic transformation by tumor suppression via the apoptosis.To verify the phenomena at a mammalian individual level, we have constructed conditional transgenic mouse with Tet-on/off system with an amino acid mutated SDHC gene. The inductions of the transgenic gene by tetracycline were found in several organs and tissues except brain and muscle. Being hyper-sensitive to oxidative stress, the transgenic mouse is anticipated as a model mouse with cancer caused by oxidative stress.