Otsubo K, Goto H, Nishio M, Kawamura K, Yanagi S, Nishie W, Sasaki T, Maehama T, Nishina H, Mimori K, Nakano T, Shimizu H, Mak T W, Nakao K, Nakanishi Y, Suzuki A
Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan.
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Oncogene. 2017 Jul 20;36(29):4201-4211. doi: 10.1038/onc.2017.58. Epub 2017 Mar 27.
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO)-Cre/Mob1a/Mob1b; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.
Mps单结合激酶激活剂（MOB）1A/1B是Hippo信号通路的核心组成部分。这些共同激活大肿瘤抑制同源激酶的蛋白质也是肿瘤抑制因子。为了研究MOB1A/B在正常生理和肺癌中的作用，我们构建了多西环素（Dox）诱导的、支气管肺泡上皮细胞特异性的MOB1A/B基因敲除小鼠（SPC-rtTA/(tetO)-Cre/Mob1a/Mob1b；称为luMob1DKO小鼠）。大多数在子宫内接受Dox的突变体（luMob1DKO (E6.5-18.5)小鼠）在出生后1小时内死于缺氧。它们的肺泡上皮细胞显示出增殖增加、YAP1/TAZ依赖的分化受损以及表面活性蛋白产生减少，所有这些都是人类呼吸窘迫综合征的特征。有趣的是，出生后接受Dox的突变小鼠（luMob1DKO (P21-41)小鼠）没有自发形成肺腺癌，并且乌拉坦治疗诱导的肺肿瘤形成减少（而非增加）。luMob1DKO (P21-41)小鼠的肺显示支气管上皮细胞的脱离增加，且被认为是引发肺腺癌的支气管肺泡干细胞数量减少。关键半桥粒成分XVII型胶原蛋白的YAP1/TAZ-NKX2.1依赖表达也降低。因此，MOB1-YAP1/TAZ-NKX2.1轴对于正常肺稳态以及肺生态位中肺泡干细胞维持所必需的XVII型胶原蛋白的表达至关重要。
