Ylikorkala A, Rossi D J, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Mäkelä T P
Molecular and Cancer Biology Program, Haartman Institute and Biomedicum Helsinki, Post Office Box 63, University of Helsinki, Helsinki 00014, Finland.
Science. 2001 Aug 17;293(5533):1323-6. doi: 10.1126/science.1062074.
The LKB1 tumor suppressor gene, mutated in Peutz-Jeghers syndrome, encodes a serine/threonine kinase of unknown function. Here we show that mice with a targeted disruption of Lkb1 die at midgestation, with the embryos showing neural tube defects, mesenchymal cell death, and vascular abnormalities. Extraembryonic development was also severely affected; the mutant placentas exhibited defective labyrinth layer development and the fetal vessels failed to invade the placenta. These phenotypes were associated with tissue-specific deregulation of vascular endothelial growth factor (VEGF) expression, including a marked increase in the amount of VEGF messenger RNA. Moreover, VEGF production in cultured Lkb1(-/-) fibroblasts was elevated in both normoxic and hypoxic conditions. These findings place Lkb1 in the VEGF signaling pathway and suggest that the vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.
LKB1肿瘤抑制基因在黑斑息肉综合征中发生突变，编码一种功能未知的丝氨酸/苏氨酸激酶。我们在此表明，Lkb1基因被靶向破坏的小鼠在妊娠中期死亡，胚胎表现出神经管缺陷、间充质细胞死亡和血管异常。胚外发育也受到严重影响；突变的胎盘表现出迷路层发育缺陷，胎儿血管无法侵入胎盘。这些表型与血管内皮生长因子（VEGF）表达的组织特异性失调有关，包括VEGF信使核糖核酸量的显著增加。此外，在常氧和低氧条件下，培养的Lkb1(-/-)成纤维细胞中的VEGF产生均升高。这些发现将Lkb1置于VEGF信号通路中，并表明伴随Lkb1缺失的血管缺陷至少部分由VEGF介导。
