Closing the circadian loop:: CLOCK-induced transcription of its own inhibitors per and tim
Closing the circadian loop:: CLOCK-induced transcription of its own inhibitors per and tim
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DOI：
10.1126/science.280.5369.1599
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发表时间：
1998-06-05
期刊：
影响因子：
56.9
通讯作者：
Kay, SA
中科院分区：
文献类型：
--
作者：
Darlington, TK;Wager-Smith, K;Kay, SA
昼夜节律振荡器以大约24小时的周期产生有节奏的输出。尽管在几个模型系统中进行了广泛的研究，但其任何组分的生化作用模式尚未得到证实。在这里，果蝇CLOCK蛋白被证明可以诱导昼夜节律基因period和timeless的转录。dCLOCK作为异源二聚体与果蝇BMAL 1同源。这些蛋白质通过周期启动子中的E-box序列起作用。无时限启动子包含一个18个碱基对的元件，包含一个E盒，这足以赋予dCLOCK对报告基因的反应性。PERIOD和TIMELESS蛋白阻断dCLOCK通过E-box反式激活其启动子的能力。因此，dCLOCK驱动period和timeless的表达，这反过来又抑制dCLOCK的活动并关闭昼夜节律循环。
The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless. dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. The timeless promoter contains an 18-base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.