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p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway


The mitogen-activated protein kinase (MAPK) p38α controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38α) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38α showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)–c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK–c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38α negatively regulates cell proliferation by antagonizing the JNK–c-Jun pathway in multiple cell types and in liver cancer development.

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Figure 1: Pups with embryo-specific deletion of p38α (Mapk14Δ/Δ) develop to term.
Figure 2: Lung dysfunction and infiltration of hematopoietic cells.
Figure 3: Mapk14Δ/Δ newborns show increased numbers of erythroblasts and granulocytes.
Figure 4: Increased c-Jun/JNK activity in Mapk14Δ/Δ fetal liver cells.
Figure 5: Increased c-Jun/JNK activity contributes to the proliferative advantage of Mapk14Δ/Δ erythroblasts.
Figure 6: Enhanced proliferation of Mapk14Δ/Δ MEFs is dependent on augmented c-Jun/JNK activity.
Figure 7: p38α suppresses liver tumor development by antagonizing the JNK–c-Jun pathway.
Figure 8: Schematic model for p38α-dependent regulation of cell proliferation through the JNK–c-Jun pathway.


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We thank H. Jiang, M. McFarland and L. Pantages-Torok at Boehringer Ingelheim for providing Mapk14f/f mice. We are grateful to F. Kiefer (Max Planck Institute for Molecular Biomedicine) for HPK1 antibodies and C. Bonny (Xigen) for the D-JNKI1 peptide sample. We thank H. Tkadletz for help with the illustrations; C. Cobaleda for help on the colony-forming assay; W. Breitwieser for qRT-PCR primers for phosphatases and D. Barlow, P. Munoz Canoves, R. Eferl, M. Sibilia, R. Ricci and the Wagner laboratory for critical reading and discussion of the manuscript. The Research Institute of Molecular Pathology is funded by Boehringer Ingelheim. L.H. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship and a Marie Curie individual fellowship. L.B. was supported by an EMBO long-term fellowship.

Author information

Authors and Affiliations



L.H. and E.F.W. designed the experiments. L.H. performed most of the experiments; L.B. performed the MEF culture and analysis; A.M. and H.B. designed and performed the erythroblast culture and analysis; N.S. and C.H. performed the microarray experiment and analysis and L.K., V.K. and H.S. performed histological staining and analysis. L.H., L.B. and E.F.W. wrote the manuscript.

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Correspondence to Erwin F Wagner.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Characterization of p38αΔ/Δ newborn lungs. (PDF 315 kb)

Supplementary Fig. 2

Cytokine expression in p38αΔ/Δ fetal livers. (PDF 260 kb)

Supplementary Fig. 3

Liver cancer development in mice with liver-specific deletion of p38α. (PDF 386 kb)

Supplementary Fig. 4

JNK activities in MEFs and expression levels of phosphatases. (PDF 284 kb)

Supplementary Table 1

Genes with altered expression levels in p38αΔ/Δ fetal liver samples. (PDF 123 kb)

Supplementary Table 2

Primers for qRT-PCR. (PDF 43 kb)

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Hui, L., Bakiri, L., Mairhorfer, A. et al. p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway. Nat Genet 39, 741–749 (2007).

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