关于Shisa直系同源基因的比较基因组学。

Katoh Yuriko, Katoh Masaru

M&M Medical BioInformatics, Hongo 113-0033, Japan.

Int J Mol Med. 2005 Jul;16(1):181-5.

WNT signaling molecules are implicated in a variety of human tumors, such as gastric cancer and colorectal cancer. FGFR2 gene, encoding FGF receptor 2, is amplified in human gastric and breast cancer. WNT and FGF signaling pathways network together during carcinogenesis and embryogenesis. Xenopus shisa is claimed to inhibit the post-translational maturation of wnt and fgf receptors. Here, we identified and characterized the rat Shisa (Tmem46) gene by using bioinformatics for comparative proteomics and comparative genomics analyses. Rat Shisa gene, consisting of two exons, was located within AC126002.4 genome sequence. Shisa gene at rat chromosome 15p12 was found to encode a type I transmembrane protein (295 aa), showing 99.3, 92.5, 81.7, 40.3 and 38.6% total-amino-acid identity with mouse Shisa, human SHISA, chicken shisa, Xenopus shisa and zebrafish shisa, respectively. The extracellular Cys-rich domain with eight Cys residues was conserved among vertebrate Shisa orthologs. The C-terminal cytoplasmic region was conserved among mammalian and chicken Shisa orthologs, but not in Xenopus and zebrafish Shisa orthologs. Human SHISA promoter and rat Shisa promoter were not conserved well. Function of human SHISA is predicted to be divergent from that of Xenopus shisa due to the protein evolution and the promoter evolution. This is the first report on the rat Shisa gene and on molecular evolution of Shisa orthologs.

WNT信号分子与多种人类肿瘤有关，如胃癌和结直肠癌。编码成纤维细胞生长因子受体2（FGF receptor 2）的FGFR2基因在人类胃癌和乳腺癌中存在扩增。WNT和FGF信号通路在肿瘤发生和胚胎发育过程中共同形成网络。非洲爪蟾Shisa被认为可抑制wnt和fgf受体的翻译后成熟。在此，我们通过生物信息学进行比较蛋白质组学和比较基因组学分析，鉴定并表征了大鼠Shisa（Tmem46）基因。大鼠Shisa基因由两个外显子组成，位于AC126002.4基因组序列内。发现大鼠15号染色体p12上的Shisa基因编码一种I型跨膜蛋白（295个氨基酸），与小鼠Shisa、人类SHISA、鸡Shisa、非洲爪蟾Shisa和斑马鱼Shisa的总氨基酸同一性分别为99.3%、92.5%、81.7%、40.3%和38.6%。具有八个半胱氨酸残基的细胞外富含半胱氨酸结构域在脊椎动物Shisa直系同源物中是保守的。C末端细胞质区域在哺乳动物和鸡的Shisa直系同源物中是保守的，但在非洲爪蟾和斑马鱼的Shisa直系同源物中不保守。人类SHISA启动子和大鼠Shisa启动子的保守性不佳。由于蛋白质进化和启动子进化，预计人类SHISA的功能与非洲爪蟾Shisa的功能不同。这是关于大鼠Shisa基因以及Shisa直系同源物分子进化的首次报道。