哺乳动物昼夜时钟中的相互作用分子循环
L P Shearman1, S Sriram, D R Weaver
1Laboratory of Developmental Chronobiology, MassGeneral Hospital for Children, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
Science (New York, N.Y.)
|May 12, 2000
概括
鼠标主昼夜时钟使用交互的反循环. PERIOD2 积极调节 BMAL1 循环,而 CRYPTOCHROMES 负面调节 Period 和 Cryptochrome 循环,揭示了关键的分子相互作用.
科学领域:
- 时间生物学 时间生物学
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 主生态时钟调节了每天的生物节奏.
- 了解昼夜钟的分子机制对于时代生物学至关重要.
- 涉及转录和翻译的反循环是生物钟的已知组成部分.
研究的目的:
- 为了阐明老鼠主昼夜钟的核心分子机制.
- 确定PERIOD2和CRYPTOCHROMES在调节昼夜节律中的作用.
- 为了研究 CLOCK:BMAL1 和 CRYPTOCHROME 蛋白质之间的相互作用.
主要方法:
- 对时钟/时钟突变小鼠,周期2(Brdm1) 突变小鼠和缺乏加密色素的小鼠的分析.
- 在不同的突变小鼠模型中评估Bmal1节奏.
- 在体外蛋白质:蛋白质相互作用测试以研究CLOCK:BMAL1转录的CRYPTOCHROME抑制.
主要成果:
- 确定了积极和消极的交互转录-翻译反循环作为小鼠昼夜时钟的核心机制.
- 证明PERIOD2在Bmal1循环的积极调节中发挥了主导作用.
- 表明,CYPTOCHROMES通过直接的蛋白质:蛋白质相互作用抑制了CLOCK:BMAL1介导的转录,独立于PERIOD和TIMELESS.
- 建立了PERIOD2作为一个积极的调节器和CRYPTOCHROMES作为负的调节器在各自的周期中.
结论:
- 鼠标主昼夜时钟通过相互连接的正 (PERIOD2) 和负 (CRYPTOCHROMES) 反循环运行.
- 在调节核心时钟基因表达和节律性方面,PERIOD2和CRYPTOCHROMES起着不同的关键作用.
- 直接的蛋白质相互作用调解了CRYPTOCHROME在CLOCK:BMAL1转录活性上的抑制功能.
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