PER-dependent rhytms in CLK phosphorylation and E-box binding regulate circadian transcription
PER-dependent rhytms in CLK phosphorylation and E-box binding regulate circadian transcription
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DOI：
10.1101/gad.1404406
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发表时间：
2006-03-15
影响因子：
10.5
通讯作者：
Hardin, PE
中科院分区：
文献类型：
--
作者：
Yu, WJ;Zheng, H;Hardin, PE
CLOCK-CYCLE (CLK-CYC) 异二聚体的转录激活和 PERIOD-TIMELESS (PER-TIM) 异二聚体的抑制对于果蝇的昼夜节律振荡功能至关重要。之前发现 PER-TIM 与 CLK-CYC 相互作用以抑制转录，在这里我们表明这种相互作用抑制 CLK-CYC 与体内 E-box 调节元件的结合。与 PER-TIM 和 CLK-CYC 之间的相互作用同时发生的是 CLK 的过度磷酸化。这种过度磷酸化与 DOUBLE-TIME (DBT) 激酶依赖 PER 进入与 CLK-CYC 的复合物同时发生，其中 DBT 使 CLK 和 PER 不稳定。一旦 PER 和 CLK 被降解，一种新的低磷酸化形式的 CLK 就会与 E-box 结合和转录激活同时积累。这些研究表明，CLK磷酸化中的PER依赖性节律控制E-box依赖性转录和CLK稳定性的节律，从而将昼夜节律周期中的PER和CLK功能联系起来，并将果蝇的转录反馈机制与哺乳动物的转录反馈机制区分开来。
Transcriptional activation by CLOCK-CYCLE (CLK-CYC) heterodimers and repression by PERIOD-TIMELESS (PER-TIM) heterodimers are essential for circadian oscillator function in Drosophila. PER-TIM was previously found to interact with CLK-CYC to repress transcription, and here we show that this interaction inhibits binding of CLK-CYC to E-box regulatory elements in vivo. Coincident with the interaction between PER-TIM and CLK-CYC is the hyperphosphorylation of CLK. This hyperphosphorylation occurs in parallel with the PER-dependent entry of DOUBLE-TIME (DBT) kinase into a complex with CLK-CYC, where DBT destabilizes both CLK and PER. Once PER and CLK are degraded, a novel hypophosphorylated form of CLK accumulates in parallel with E-box binding and transcriptional activation. These studies suggest that PER-dependent rhythms in CLK phosphorylation control rhythms in E-box-dependent transcription and CLK stability, thus linking PER and CLK function during the circadian cycle and distinguishing the transcriptional feedback mechanism in flies from that in mammals.