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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock
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CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock

机译：CKIε/δ依赖的磷酸化是哺乳动物生物钟中对温度不敏感的周期确定过程

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摘要

A striking feature of the circadian clock is its flexible yet robust response to various environmental conditions. To analyze the biochemical processes underlying this flexible-yet-robust characteristic, we examined the effects of 1,260 pharmacologically active compounds in mouse and human clock cell lines. Compounds that markedly (>10 s.d.) lengthened the period in both cell lines, also lengthened it in central clock tissues and peripheral clock cells. Most compounds inhibited casein kinase 1ε (CKIε) or CKIδ phosphorylation of the PER2 protein. Manipulation of CKIε/δ-dependent phosphorylation by these compounds lengthened the period of the mammalian clock from circadian (24 h) to circabidian (48 h), revealing its high sensitivity to chemical perturbation. The degradation rate of PER2, which is regulated by CKIε/δ-dependent phosphorylation, was temperature-insensitive in living clock cells, yet sensitive to chemical perturbations. This temperature-insensi-tivity was preserved in the CKIε/δ-dependent phosphorylation of a synthetic peptide in vitro. Thus, CKIε/δ-dependent phosphorylation is likely a temperature-insensitive period-determining process in the mammalian circadian clock.
机译：该生物钟的显着特征是其对各种环境条件的灵活而强大的响应。为了分析这种灵活而强大的特征背后的生化过程，我们研究了1,260种药理活性化合物在小鼠和人类时钟细胞系中的作用。明显（> 10 s.d.）的化合物延长了两个细胞系的周期，也延长了中央时钟组织和外围时钟细胞的周期。大多数化合物抑制PER2蛋白的酪蛋白激酶1ε（CKIε）或CKIδ磷酸化。这些化合物对CKIε/δ依赖性磷酸化的操纵将哺乳动物生物钟的周期从昼夜节律（24小时）延长到昼夜节律（48小时），显示了其对化学扰动的高度敏感性。 PER2的降解速率受CKIε/δ依赖性磷酸化调节，在活的时钟单元中对温度不敏感，但对化学扰动敏感。在体外，合成肽的CKIε/δ依赖性磷酸化保留了这种温度敏感性。因此，在哺乳动物生物钟中，依赖CKIε/δ的磷酸化可能是温度不敏感的周期确定过程。

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  • 作者

    Yasushi lsojima; Masato Nakajima; Hideki Ukai; Hiroshi Fujishima; Rikuhiro G. Yamada; Koh-hei Masumoto; Reiko Kiuchi; Mayumi lshida; Maki Ukai-Tadenuma; Yoichi Minami; Ryotaku Kito; Kazuki Nakao; Wataru Kishimoto; Seung-Hee Yoo; Kazuhiro Shimomura; Toshifumi Takao; Atsuko Takano; Toshio Kojima; Katsuya Nagai; Yoshiyuki Sakaki; Joseph S. Takahashi; Hiroki R. Ueda;

  • 作者单位

    Comparative Systems Biology Team, Genomic Science Center, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan Developmental Systems Modeling Team, Advanced Computational Sciences Department, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Comparative Systems Biology Team, Genomic Science Center, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan Developmental Systems Modeling Team, Advanced Computational Sciences Department, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Animal Resource Unit, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan;

    Howard Hughes Medical Institute, Northwestern University, 2205 Tech Drive, Evanston, IL 60208 Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111;

    Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208 Center for Functional Genomics, Northwestern University, 2205 Tech Drive, Evanston, IL 60208;

    Laboratory of Protein Profiling and Functional Proteomics,Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan;

    Laboratory of Proteins Involved in Homeostatic Integration, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan;

    Comparative Systems Biology Team, Genomic Science Center, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;

    Laboratory of Proteins Involved in Homeostatic Integration, Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan;

    Comparative Systems Biology Team, Genomic Science Center, RIKEN, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan;

    Howard Hughes Medical Institute, Northwestern University, 2205 Tech Drive, Evanston, IL 60208 Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208 Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111 Center for Functional Genomics, Northwestern University, 2205 Tech Drive, Evanston, IL 60208;

    Laboratory for Systems Biology, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan Functional Genomics Unit, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan Department of Bioscience, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    chemical biological approach; temperature compensation;

    机译：化学生物学方法;温度补偿;

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