The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression

Abstract

Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRasG12D-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.

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Figure 1: MKK7 controls onset, incidence and progression of KRasG12D-driven lung tumorigenesis.
Figure 2: Mapk8+/−; Mapk9−/− compound mutant mice phenocopy the effect of MKK7 deletion.
Figure 3: The MKK7-JNK pathway controls p53 expression in lung cancer.
Figure 4: MKK7 regulates senescence and p53 stability.
Figure 5: Loss of MKK7 can be rescued by overexpression of p53.
Figure 6: MKK7 controls onset and incidence of NeuT-driven mammary cancer.

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Acknowledgements

We thank all members of our laboratories for discussions; H. Scheuch and M. Radolf for microarray support; and E. Wagner for reading the manuscript. D.S. is supported by the EU INFLA-CARE network. J.M.P. is supported by grants from IMBA, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, GEN-AU (AustroMouse) and an EU ERC Advanced Grant. V.G.G. and A.K. are supported by the EU-grants INFLA-CARE and GENICA.

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D.S. designed and performed most experiments. A.K. and V.G.G. performed the DNA damage and p53 immunohistochemistry and analysis. A.M. performed all RT-PCR analyses. T.W. generated the MKK7floxed mice. U.E. and V.S. helped with immunohistochemistry. R.-H.Z. analyzed the tumor section as the expert pathologist. J.A.P. and G.G.N. helped in microarray and gene set enrichment analysis. G.F. and M.S. contributed to the characterization of the ErbB-2 and Super p53 transgenic mice, respectively. J.M.P. coordinated the project and wrote the manuscript with D.S.

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Correspondence to Josef M Penninger.

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The authors declare no competing financial interests.

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Schramek, D., Kotsinas, A., Meixner, A. et al. The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nat Genet 43, 212–219 (2011). https://doi.org/10.1038/ng.767

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