Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors.
Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors.
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小鼠 Serca2 的新型等位基因突变诱导鳞状细胞肿瘤的差异发展。
DOI：
10.1016/j.bbrc.2016.04.136
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Noda T
中科院分区：
文献类型：
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作者：
Toki H,Minowa O;Inoue M;Motegi H;Karashima Y;Ikeda A;Kaneda H;Sakuraba Y;Saiki Y;Wakana S;Suzuki H;Gondo Y;Shiroishi T;Noda T
编码肌浆网钙ATP酶的Serca 2基因的显性突变使小鼠易患胃肠道上皮癌[1-4]，使人类易患Darier病（DD）[1 - 4 -17]。在这项研究中，我们产生了小鼠窝藏N-乙基-N-亚硝基脲（ENU）诱导的等位基因突变Serca 2：三个错义突变和一个无义突变。携带这些Serca 2突变的小鼠发生的肿瘤被归类为早发性鳞状细胞肿瘤（SCT），其发展类似于空型敲除小鼠[2，4]（侵袭性形式; M682，M814）或迟发性肿瘤（轻度形式; M1049，M1162）。分子生物学分析表明，Serca 2的mRNA或蛋白质的表达水平在正常食管细胞的任何四个突变杂合子没有畸变。有没有在鳞状细胞癌的Serca 2位点的杂合性丢失的四个线。使用原子结构模型和累积的突变蛋白研究预测每个突变对Ca 2 +-ATP酶活性的影响，这表明假定Serca 2酶活性的完全丧失可能导致早期肿瘤发作，而Serca 2保留残余酶活性的突变导致晚期发作。我们认为，受损Serca 2基因产物活性通过一种尚未认识到但常见的调控途径对鳞状细胞癌发生有长期影响，从发病到最终的癌阶段。
Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca2+-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impairedSerca2gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway.