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

Institute of Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohrgasse 3-5, A-1030 Vienna, Austria.
Nature Cell Biology (Impact Factor: 20.06). 04/2004; 6(3):215-26. DOI: 10.1038/ncb1098
Source: PubMed

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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Available from: Hai-Ying Mary Cheng, Jun 12, 2014
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    • "It has been shown that CDC2 is a downstream target for the MKK7-JNK-cJun signaling pathway. Further, loss of c-Jun results in reduced CDC2 expression, cell cycle arrest in the G2/M phase, and impaired cell proliferation [18]. In this study, we found an accumulation of LH2171-treated BJAB cells in the G2/M phase (Figure 3C), and LH2171 treatment dramatically decreased CDC2 expression in BJAB cells (Figure 4C). "
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    ABSTRACT: Lactobacillus helveticus SBT2171 (LH2171) is a lactic acid bacterium with high protease activity and used in starter cultures in the manufacture of cheese. We recently reported that consumption of cheese manufactured using LH2171 alleviated symptoms of dextran sodium sulfate (DSS)-induced colitis in mice. In this study, we have examined whether LH2171 itself exerts an inhibitory effect on the excessive proliferation of lymphocytes. We found that LH2171 inhibited the proliferation of LPS-stimulated mouse T and B cells, and the human lymphoma cell lines, Jurkat and BJAB. Cell cycle analysis showed an accumulation of LH2171-treated BJAB cells in the G2/M phase. Further, phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun was reduced by LH2171 in BJAB cells. Subsequently, expression of cell division cycle 2 (CDC2), regulated by the JNK signaling pathway and essential for G2/M phase progression, was inhibited by LH2171. It was also demonstrated that intraperitoneal administration of LH2171 strongly alleviated symptoms of collagen-induced arthritis (CIA) in mice. These findings suggest that LH2171 inhibits the proliferation of lymphocytes through a suppression of the JNK signaling pathway and exerts an immunosuppressive effect in vivo.
    PLoS ONE 09/2014; 9(9):e108360. DOI:10.1371/journal.pone.0108360 · 3.23 Impact Factor
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    • "Genetic ablation of Mkk4 in mice leads to lethality between embryonic day 10.5 (E10.5) and E12.5, and the knockout embryos display severe anemia, abnormal hepatogenesis and liver cell apoptosis.6-8 Genetic ablation of Mkk7 also leads to embryonic lethality, but in this case, the knockout embryos die between E11.5 and E13.5 due to disorganized liver and decreased hepatocyte proliferation.9 Hence, MKK4 and MKK7 are both essential for embryonic survival, but they make different contributions to the developmental programs, so that MKK4 cannot compensate for loss of MKK7, and vice versa. "
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    ABSTRACT: In vivo gene knockout studies in mice have revealed essential roles of the mitogen-activated protein kinases (MAPKs) in embryogenesis, but due to early lethality of the knockout embryos, the underlying mechanisms and specific developmental programs regulated by the MAPK pathways have remained largely unknown. In vitro differentiation of mouse embryonic stem cells (ESCs) have opened new possibilities for understanding lineage segregation and gene function in the developmental stages that are not normally accessible in vivo. Building on this technology, in combination with gene knockout cells, we investigated the roles of MKK4 and MKK7, two upstream kinases of the MAPKs, in early lineage specification. Our results show that MKK4 and MKK7 differentially regulate the JNK and p38 MAPKs and make distinct contributions to differentiation programs. In vitro ESC differentiation is a valuable system to investigate the molecular and signaling mechanisms of early embryogenesis.
    Communicative & integrative biology 07/2012; 5(4):319-24. DOI:10.4161/cib.20216
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    • "The c-jun NH2 terminal kinases (JNK), among other MAPKs are activated by anti-tubulin drugs in many cancer cells [6], [7], [8], [9], [10], [11]. Furthermore, there is evidence indicating that JNK is activated during the normal course of mitosis and plays a role in some stages of mitosis [10], [12], [13], [14], [15], [16]. Among three JNKs, JNK1 and JNK2 are ubiquitously expressed and thought to have distinct and overlapping roles in diverse settings. "
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    ABSTRACT: Some anti-cancer drugs, including those that alter microtubule dynamics target mitotic cells and induce apoptosis in some cell types. However, such drugs elicit protective responses in other cell types allowing cells to escape from drug-induced mitotic inhibition. Cells with a faulty protective mechanism undergo defective mitosis, leading to genome instability. Brd4 is a double bromodomain protein that remains on chromosomes during mitosis. However, Brd4 is released from mitotic chromosomes when cells are exposed to anti-mitotic drugs including nocodazole. Neither the mechanisms, nor the biological significance of drug-induced Brd4 release has been fully understood. We found that deletion of the internal C-terminal region abolished nocodazole induced Brd4 release from mouse P19 cells. Furthermore, cells expressing truncated Brd4, unable to dissociate from chromosomes were blocked from mitotic progression and failed to complete cell division. We also found that pharmacological and peptide inhibitors of the c-jun-N-terminal kinases (JNK) pathway, but not inhibitors of other MAP kinases, prevented release of Brd4 from chromosomes. The JNK inhibitor that blocked Brd4 release also blocked mitotic progression. Further supporting the role of JNK in Brd4 release, JNK2-/- embryonic fibroblasts were defective in Brd4 release and sustained greater inhibition of cell growth after nocodazole treatment. In sum, activation of JNK pathway triggers release of Brd4 from chromosomes upon nocodazole treatment, which mediates a protective response designed to minimize drug-induced mitotic stress.
    PLoS ONE 05/2012; 7(5):e34719. DOI:10.1371/journal.pone.0034719 · 3.23 Impact Factor
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