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MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation

Oncogene volume 36, pages 4201–4211 (2017)Cite this article

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Abstract

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/Mob1aflox/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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Acknowledgements

We are grateful to Dr Jeffrey A Whitsett (Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, USA) for giving us SPC-rtTA/(tetO)7-Cre mice, and to A Fujimoto, M Kamihashi and M Suzuki (all of Kyushu Univ.), S Maegawa, J Utsumi, F Ishikawa, M Seiki and T Noda (all of AMED), for expert technical assistance and helpful discussions. 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).

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Author notes

  1. K Otsubo and H Goto: These authors contributed equally as first authors.

Authors and Affiliations

  1. Division of Cancer Genetics, Medical Institute of Bioregulation, Fukuoka, Japan

    K Otsubo, H Goto, M Nishio & A Suzuki

  2. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    K Otsubo & Y Nakanishi

  3. Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan

    M Nishio & A Suzuki

  4. Faculty of Science and Engineering, Waseda University, Tokyo, Japan

    K Kawamura

  5. Division of Neurology, Department of Internal Medicine, Respirology, Endocrinology and Metabolism, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan

    S Yanagi

  6. Department of Dermatology, Hokkaido University, Graduate School of Medicine, Sapporo, Japan

    W Nishie & H Shimizu

  7. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan

    T Sasaki

  8. Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan

    T Maehama

  9. Department of Developmental and Regenerative Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    H Nishina

  10. Department of Surgery, Kyushu University, Beppu Hospital, Beppu, Oita, Japan

    K Mimori

  11. Department of Pathology, Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan

    T Nakano

  12. The Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada

    T W Mak

  13. Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

    K Nakao

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Otsubo, K., Goto, H., Nishio, M. et al. MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. Oncogene 36, 4201–4211 (2017). https://doi.org/10.1038/onc.2017.58

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