title: Involvement of stress kinase mitogen-activated protein kinase kinase 7 in regulation of mammalian circadian clock.
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.
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Uchida
authors.forename: Tomomi
authors.initials: T
authors.lastname: Osaki
authors.forename: Tokiwa
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Tadanori
authors.initials: T
authors.lastname: Shimomura
authors.forename: Shoji
authors.initials: S
authors.lastname: Hata
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Horikawa
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Todo
authors.forename: Jun
authors.initials: J
authors.lastname: Hirayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
mesh_terms: D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D055550:Protein Stability; D059748:Proteolysis; D054875:Ubiquitination / Q000502:physiology
chemical_list: C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D048149:Casein Kinase 1 epsilon; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; C482570:Map2k7 protein, mouse