Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2 pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility
Haploinsufficiency of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2 pump, predisposes mice to squamous cell tumors via a novel mode of cancer susceptibility
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DOI：
10.1158/0008-5472.can-05-0026
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Shull, GE
中科院分区：
文献类型：
--
作者：
Prasad, V;Boivin, GP;Shull, GE
编码肌浆网Ca 2 +-ATP酶亚型2（SERCA 2）的Atp 2a 2或ATP 2A 2基因的一个拷贝中的无效突变导致小鼠鳞状细胞肿瘤和人类Darier病，这是一种也涉及角质形成细胞的皮肤病。在这里，我们研究了突变动物肿瘤发展的时间进程和遗传机制。Atp 2a 2（+/-）小鼠早在2月龄时就在正常前胃中过度表达与角质形成细胞过度活化相关的角蛋白。到5至7个月大时，22%的突变体发生了前胃乳头状瘤，89%的14个月以上的突变体发生了鳞状细胞乳头状瘤和/或癌，后者占优势。肿瘤发生在上皮角化的区域，并受到反复的机械刺激。肿瘤发生的遗传机制不涉及杂合性丢失，因为通过激光捕获显微切割分析的肿瘤细胞含有野生型Atp 2a 2等位基因。此外，免疫印迹和免疫组化分析表明，肿瘤角质形成细胞表达SERCA 2蛋白。在ras原癌基因中未观察到突变;然而，野生型ras表达上调，K-ras水平特别高。p53肿瘤抑制基因的丢失发生在单个巨大肿瘤中，而其他肿瘤的p53蛋白水平升高，但p53基因没有突变。这些发现表明SERCA 2单倍不足通过一种新的癌症易感性模式使小鼠易于发生肿瘤，该模式涉及AtP 2a 2（+/-）小鼠角化上皮的致瘤潜力的整体变化。
A null mutation in one copy of the Atp2a2 or ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), leads to squamous cell tumors in mice and to Darier disease in humans, a skin disorder that also involves keratinocytes. Here, we examined the time course and genetic mechanisms of tumor development in the mutant animals. Atp2a2(+/-) mice overexpressed keratins associated with keratinocyte hyperactivation in normal forestomachs as early as 2 months of age. By the age of 5 to 7 months, 22% of mutants had developed papillomas of the forestomach, and 89% of mutants older than 14 months had developed squamous cell papillomas and/or carcinomas, with a preponderance of the latter. Tumors occurred in regions that had keratinized epithelium and were subjected to repeated mechanical irritation. The genetic mechanism of tumorigenesis did not involve loss of heterozygosity, as tumor cells analyzed by laser capture microdissection contained the wild-type Atp2a2 allele. Furthermore, immunoblot and immunohistochemical analysis showed that tumor keratinocytes expressed the SERCA2 protein. Mutations were not observed in the ras proto-oncogenes; however, expression of wild-type ras was up-regulated, with particularly high levels of K-ras. Loss of the p53 tumor suppressor gene occurred in a single massive tumor, whereas other tumors had increased levels of p53 protein but no mutations in the p53 gene. These findings show that SERCA2 haploinsufficiency predisposes mice to tumor development via a novel mode of cancer susceptibility involving a global change in the tumorigenic potential of keratinized epithelium in AtP2a2(+/-) mice.