Hung Hsiu-Cheng, Maurer Christian, Kay Steve A, Weber Frank
Biochemie-Zentrum Heidelberg, Ruprecht-Karls Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
J Biol Chem. 2007 Oct 26;282(43):31349-57. doi: 10.1074/jbc.M702319200. Epub 2007 Jul 16.
The circadian clock orchestrates physiological and behavioral activities, including metabolism, neuronal activity, and cell proliferation in synchrony with the environmental cycle of day and night. Here we show that the Drosophila ortholog of the CBP/p300 family of transcription co-activators, nejire (nej), is an intrinsic component of the circadian clock that performs regulatory functions for circadian controlled transcription. Screening of overexpression mutants revealed that gain of nej function was associated with a loss of behavioral and molecular rhythms. Overexpression of NEJ suppresses the long period phenotype of a mutation in the clock gene period (per). NEJ physically interacts through two binding sites with CLOCK and the CLOCK. CYCLE (CLK.CYC) complex. Induction of CLK.CYC-dependent transcripts upon induction of nej expression from a heat-shock promoter showed that NEJ is limiting. Reduced CLK.CYC-mediated transcription in a nej hypomorphic mutant indicates an essential function of NEJ/CBP for CLK.CYC activity and a regulation of circadian transcription by availability of the co-activator. Competition for recruitment of NEJ/CBP provides a potential mechanism for cross-talk between circadian transcription and other CBP-dependent physiological processes.
生物钟协调生理和行为活动，包括新陈代谢、神经元活动以及细胞增殖，使其与昼夜环境周期同步。在此我们表明，转录共激活因子CBP/p300家族的果蝇直系同源物nejire（nej）是生物钟的一个内在组成部分，它对生物钟控制的转录发挥调节功能。对过表达突变体的筛选显示，nej功能的增强与行为和分子节律的丧失有关。NEJ的过表达抑制了生物钟基因周期（per）突变体的长周期表型。NEJ通过两个结合位点与CLOCK以及CLOCK-CYCLE（CLK.CYC）复合体发生物理相互作用。从热休克启动子诱导nej表达后，CLK.CYC依赖性转录本的诱导表明NEJ是限制性的。在nej低表达突变体中CLK.CYC介导的转录减少，这表明NEJ/CBP对CLK.CYC活性具有重要作用，并且共激活因子的可用性对生物钟转录具有调节作用。NEJ/CBP募集的竞争为生物钟转录与其他CBP依赖性生理过程之间的相互作用提供了一种潜在机制。
