Wada, T. et al. MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat. Cell Biol. 6, 215-226

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: 19.68). 04/2004; 6(3):215-26. DOI: 10.1038/ncb1098
Source: PubMed


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.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines and demonstrates great specificity to JNK, whereas MKK4 activates both JNK and p38 [36]. MKK4 and MKK7 are both involved in embryonic development, as disrupting either leads to early embryonic lethality [37] [38]. Genetic deletion of either Jnk1 or Jnk2 alone or together with Jnk3 produces viable mice, while compound deletion of Jnk1 and Jnk2 leads to early embryonic lethality, a stage too early for epidermal phenotypic assessment [39] [40]. "
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    ABSTRACT: The c-Jun N-terminal Kinases (JNK), along with Erk and p38, constitute the principle members of the mitogen-activated protein kinase (MAPK) family. JNK functions primarily through AP1 family transcription factors to regulate a plethora of cellular processes, including cell proliferation, differentiation, survival and migration. It also cross-talks and integrates with other signaling pathways in a cell context-specific and cell type-specific manner. The current views of JNK function in various skin cancers and the need of developing JNK subunit-specific inhibitors for cancer type-specific applications have been summarized in this review.
    Full-text · Article · Dec 2012 · American Journal of Cancer Research
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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.
    Full-text · Article · Jul 2012 · Communicative & integrative biology
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