Recent advances suggest that the molecular components of the circadian clock generate a self-sustaining transcriptional–translational feedback loop with a period of approx. 24 h. The precise expression profiles of human clock genes and their products have not been elucidated. We cloned human clock genes, including per1, per2, per3, cry2 and clock, and evaluated their circadian mRNA expression profiles in WI-38 fibroblasts stimulated with serum. Transcripts of hPer1, hPer2, hPer3, hBMAL1 and hCry2 (where h is human) underwent circadian oscillation. Serum-stimulation also caused daily oscillations of hPER1 protein and the apparent molecular mass of hPER1 changed. Inhibitor studies indicated that the CKI (casein kinase I) family, including CKI∊ and CKIδ, phosphorylated hPER1 and increased the apparent molecular mass of hPER1. The inhibition of hPER1 phosphorylation by CKI-7 [N-(2-aminoethyl)-5-chloro-isoquinoline-8-sulphonamide], a CKI inhibitor, disturbed hPER1 degradation, delayed the nuclear entry of hPER1 and allowed it to persist for longer in the nucleus. Furthermore, proteasome inhibitors specifically blocked hPER1 degradation. However leptomycin B, an inhibitor of nuclear export, did not alter the degradation state of hPER1 protein. These findings indicate that circadian hPER1 degradation through a proteasomal pathway can be regulated through phosphorylation by CKI, but not by subcellular localization.
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Research Article|
May 15 2004
Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts Available to Purchase
Koyomi MIYAZAKI;
Koyomi MIYAZAKI
1
*Clock Cell Biology Group, IBRF (Institute for Biological Resource and Function), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba central 6, 1-1-1, Higashi, Tsukuba, 305-8566, Japan
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Takahiro NAGASE;
Takahiro NAGASE
1
†Kazusa DNA Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan
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Miho MESAKI;
Miho MESAKI
*Clock Cell Biology Group, IBRF (Institute for Biological Resource and Function), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba central 6, 1-1-1, Higashi, Tsukuba, 305-8566, Japan
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Junko NARUKAWA;
Junko NARUKAWA
*Clock Cell Biology Group, IBRF (Institute for Biological Resource and Function), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba central 6, 1-1-1, Higashi, Tsukuba, 305-8566, Japan
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Osamu OHARA;
Osamu OHARA
†Kazusa DNA Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan
‡RIKEN Research Center for Allergy and Immunology, 1-17-22, Suehiro, Tsurumi-ku, Yokohama, 230-0045, Japan
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Norio ISHIDA
Norio ISHIDA
2
*Clock Cell Biology Group, IBRF (Institute for Biological Resource and Function), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba central 6, 1-1-1, Higashi, Tsukuba, 305-8566, Japan
§Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama, 226-8501, Japan
2To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
August 27 2003
Revision Received:
January 05 2004
Accepted:
January 29 2004
Accepted Manuscript online:
January 29 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 380 (1): 95–103.
Article history
Received:
August 27 2003
Revision Received:
January 05 2004
Accepted:
January 29 2004
Accepted Manuscript online:
January 29 2004
Citation
Koyomi MIYAZAKI, Takahiro NAGASE, Miho MESAKI, Junko NARUKAWA, Osamu OHARA, Norio ISHIDA; Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. Biochem J 15 May 2004; 380 (1): 95–103. doi: https://doi.org/10.1042/bj20031308
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