Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock

Yoshimi Uchida, Tomomi Osaki, Tokiwa Yamasaki, Tadanori Shimomura, Shoji Hata, Kazumasa Horikawa, Shigenobu Shibata, Takeshi Todo, Jun Hirayama, Hiroshi Nishina

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17 Citations (Scopus)

Abstract

The stress kinase mitogen-activated protein kinase kinase 7 (MKK7) is a specific activator of c-Jun N-terminal kinase (JNK), which controls various physiological processes, such as cell proliferation, apoptosis, differentiation, and migration. Here we show that genetic inactivation of MKK7 resulted in an extended period of oscillation in circadian gene expression in mouse embryonic fibroblasts. Exogenous expression in cultured mammalian cells of an MKK7-JNK fusion protein that functions as a constitutively active form of JNK induced phosphorylation of PER2, an essential circadian component. Furthermore, JNK interacted with PER2 at both the exogenous and endogenous levels, and MKK7-mediated JNK activation increased the half-life of PER2 protein by inhibiting its ubiquitination. Notably, the PER2 protein stabilization induced by MKK7-JNK fusion protein reduced the degradation of PER2 induced by casein kinase 1ε. Taken together, our results support a novel function for the stress kinase MKK7 as a regulator of the circadian clock in mammalian cells at steady state.

Original languageEnglish
Pages (from-to)8318-8326
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number11
DOIs
Publication statusPublished - 2012 Mar 9

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Uchida, Y., Osaki, T., Yamasaki, T., Shimomura, T., Hata, S., Horikawa, K., Shibata, S., Todo, T., Hirayama, J., & Nishina, H. (2012). Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock. Journal of Biological Chemistry, 287(11), 8318-8326. https://doi.org/10.1074/jbc.M111.308908