Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis
Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis
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DOI：
10.1073/pnas.122254599
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发表时间：
2002-06-25
影响因子：
11.1
通讯作者：
Suzuki, H
中科院分区：
文献类型：
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作者：
Jishage, K;Nezu, J;Suzuki, H
Peutz-Jeghers综合征(PJS)是一种以胃肠道错构瘤样息肉和皮肤黏膜黑色素沉着为主要特征的遗传性疾病。LKB1(STK11)丝氨酸/苏氨酸激酶是PJS致病基因的产物，已定位于染色体19p13.3。然而，一些研究得出的结果与LKB1基因突变与PJS之间的联系并不一致。我们构建了Lkb1基因的敲除突变，以确定它是否是PJS的致病基因，并检测Lkb1基因的生物学作用。LKB1(-/-)小鼠在性交后8.5至9.5天内死于宫内。在性交后9.0天，Lkb1(-/-)胚胎一般比同龄的小鼠小，表现出发育迟缓，并且没有发生胚胎转变。在10到14个月龄的Lkb1(+/-)小鼠中观察到多发性胃腺瘤性息肉。我们的结果表明，有功能的Lkb1是正常胚胎发育所必需的，并且与肿瘤的发生有关。Lkb1(+/-)小鼠适合于研究PJS遗传性胃肿瘤发生的分子机制。
Peutz-Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine/threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1(-/-) mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1(-/-) embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10- to 14-month-old Lkb1(+/-) mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1(+/-) mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.