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p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation

Nature Genetics volume 39, pages 750–758 (2007)Cite this article

Abstract

Stem cell function is central for the maintenance of normal tissue homeostasis. Here we show that deletion of p38α mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation and defective differentiation of lung stem and progenitor cells both in vivo and in vitro. We found that p38α positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. In addition, p38α controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. As a consequence, the inactivation of p38α leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-RasG12V-induced tumorigenesis. Our results indicate that by coordinating proliferation and differentiation signals in lung stem and progenitor cells, p38α has a key role in the regulation of lung cell renewal and tumorigenesis.

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Figure 1: Genetic inactivation of Mapk14 in adult mice.
Figure 2: Inactivation of Mapk14 affects lung morphology in adult mice.
Figure 3: Deregulation of differentiation and proliferation pathways in Mapk14-null lungs.
Figure 4: p38α inhibits proliferation of lung progenitor cells.
Figure 5: Regulation of lung stem and progenitor cell homeostasis by p38α.
Figure 6: K-RasG12V-induced lung tumorigenesis in Mapk14Δ/Δ mice.
Figure 7: Downregulation of p38α enhances lung tumorigenesis.
Figure 8: Regulation of lung stem and progenitor cell function by p38α.

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Acknowledgements

The targeting vector was generated while E.P. and A.R.N. were working at the EMBL (Heidelberg). We are grateful to M. Morente and the CNIO Tumor Bank Network for providing human samples of tumoral and normal lungs and T. Graf (CRG) for the C/EBPα expression construct. We thank A. Garcia and J. Sanchez for technical help with the mouse colony and histological work, respectively. J.J.V. is an investigator of the Ramon y Cajal Programme. This work was funded by grants to A.R.N. from the Spanish Ministerio de Educación y Ciencia, Marató-TV3 and the Fundación Científica de la Asociación Española Contra el Cáncer.

Author information

Author notes

  1. Eusebio Perdiguero

    Present address: Current address: Center for Genomic Regulation (CRG), E08003 Barcelona, Spain.,

  2. Stephan Tenbaum and Eusebio Perdiguero: These authors contributed equally to this work.

Authors and Affiliations

  1. CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, Madrid, 28029, Spain

    Juan José Ventura, Stephan Tenbaum, Eusebio Perdiguero, Carmen Guerra, Mariano Barbacid & Angel R Nebreda

  2. European Molecular Biology Laboratory (EMBL) Mouse Biology Unit, via Ramarini 32, Monterotondo, 00016, Italy

    Marion Huth & Manolis Pasparakis

  3. Institute for Genetics, University of Cologne, Zulpicher Str. 47, Cologne, 50674, Germany

    Manolis Pasparakis

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Contributions

J.J.V. and A.R.N. designed the research; J.J.V. performed the research; S.T. provided technical support and managed the mouse colony; E.P. generated the p38α targeting vector; C.G. and M.B. contributed essential tools and advice; M.H. and M.P. generated the p38α floxed mice; J.J.V. and A.R.N. interpreted the results and wrote the paper.

Corresponding authors

Correspondence to Juan José Ventura or Angel R Nebreda.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Biochemical changes in lungs from p38α-deficient mice. (PDF 193 kb)

Supplementary Fig. 2

Isolation and characterization of lung stem and progenitor cells. (PDF 274 kb)

Supplementary Fig. 3

Histological analysis of K-RasG12V-induced tumorigenesis in p38α-deficient lungs. (PDF 860 kb)

Supplementary Table 1

RT-PCR primer sequences. (PDF 39 kb)

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Ventura, J., Tenbaum, S., Perdiguero, E. et al. p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet 39, 750–758 (2007). https://doi.org/10.1038/ng2037

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