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MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence

Abstract

During the development of multicellular organisms, concerted actions of molecular signalling networks determine whether cells undergo proliferation, differentiation, death or ageing. Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic lethality and impaired proliferation of hepatocytes. Beginning at passage 4–5, mkk7−/− mouse embryonic fibroblasts (MEFs) display impaired proliferation, premature senescence and G2/M cell cycle arrest. Similarly, loss of c-Jun or expression of a c-JunAA mutant in which the JNK phosphorylation sites were replaced with alanine results in a G2/M cell-cycle block. The G2/M cell-cycle kinase CDC2 was identified as a target for the MKK7–JNK–c-Jun pathway. These data show that the MKK7–JNK–c-Jun signalling pathway couples developmental and environmental cues to CDC2 expression, G2/M cell cycle progression and cellular senescence in fibroblasts.

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Figure 1: Impaired liver development in mkk7−/− embryos.
Figure 2: Decreased proliferation and premature senescence of mkk7−/− MEFs.
Figure 3: MKK7 is required to protect cells from premature senescence.
Figure 4: Loss of MKK7 results in decreased CDC2 expression and reduced CDC2 kinase activity.
Figure 5: MKK7 controls cdc2 promoter activity.
Figure 6: c-Jun regulates CDC2 expression.
Figure 7: c-Jun rescues senescence and proliferation defects in mkk7−/− MEFs.

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Acknowledgements

We thank J. Woodgett, L. Harrington, J. C. Zuniga-Pflucker, T. Schmitt, J. Joza, C. Krawczyk, E. Griffith, L. Barra, M. Crackower, U. Erickson, L. Zhang, H. Hara and M. Rangachari for discussion and reagents. T.W. is supported by the H15th fellowship of the Japan Society for the Promotion of Science. This work is supported by the National Cancer Institute of Canada (NCIC), the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), and the Jubilaeumsfonds of the Austrian National Bank.

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Wada, T., Joza, N., Cheng, Hy. et al. MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat Cell Biol 6, 215–226 (2004). https://doi.org/10.1038/ncb1098

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