Abstract
The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 abrogates BMAL1 phosphorylation and lengthens circadian period in fibroblasts. Mice deficient for neuron-specific isoform JNK3 have altered behavioural rhythms, with longer free-running period and compromised phase shifts to light. The locomotor rhythms are insensitive to intensity variance of constant light, deviating from Aschoff's rule. Thus, JNK regulates a core characteristic of the circadian clock by controlling the oscillation speed and the phase in response to light.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors / metabolism
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Animals
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Cell Line
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Circadian Clocks / physiology
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Humans
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Immunoblotting
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Immunoprecipitation
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Mammals / metabolism
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Mammals / physiology
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Mice
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Mitogen-Activated Protein Kinase 10 / genetics
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Mitogen-Activated Protein Kinase 10 / metabolism
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / metabolism
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Mitogen-Activated Protein Kinase 9 / genetics
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Mitogen-Activated Protein Kinase 9 / metabolism
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Motor Activity / physiology
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NIH 3T3 Cells
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Phosphorylation / genetics
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Phosphorylation / physiology
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Suprachiasmatic Nucleus / metabolism
Substances
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ARNTL Transcription Factors
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Mitogen-Activated Protein Kinase 10
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Mitogen-Activated Protein Kinase 9
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 8