TY - JOUR
T1 - MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation
AU - Otsubo, K.
AU - Goto, H.
AU - Nishio, M.
AU - Kawamura, K.
AU - Yanagi, S.
AU - Nishie, W.
AU - Sasaki, T.
AU - Maehama, T.
AU - Nishina, H.
AU - Mimori, K.
AU - Nakano, T.
AU - Shimizu, H.
AU - Mak, T. W.
AU - Nakao, K.
AU - Nakanishi, Y.
AU - Suzuki, A.
N1 - Funding Information:
This work was supported by MEXT and JSPS (grants 26860214 to MN, 24240120 to AS and HG); the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University; P-DiRECT (grants 11088019 to AS); AMED (grants 16770279 to AS and HG); and the Uehara Memorial Foundation (to AS).
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature.
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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) 7-Cre/Mob1a flox/flox/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.
AB - 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) 7-Cre/Mob1a flox/flox/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.
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U2 - 10.1038/onc.2017.58
DO - 10.1038/onc.2017.58
M3 - Article
C2 - 28346423
AN - SCOPUS:85016108844
SN - 0950-9232
VL - 36
SP - 4201
EP - 4211
JO - Oncogene
JF - Oncogene
IS - 29
ER -
