LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1
LARK activates posttranscriptional expression of an essential mammalian clock protein, PERIOD1
复制标题
DOI：
10.1073/pnas.0607567104
复制
发表时间：
2007-02-06
影响因子：
11.1
通讯作者：
Tei, Hajime
中科院分区：
文献类型：
--
作者：
Kojima, Shihoko;Matsumoto, Ken;Tei, Hajime
哺乳动物分子钟由反馈回路组成，以保持 24 小时昼夜节律。尽管人们的注意力集中在转录调控上，但很明显转录后控制在分子生物钟中也发挥着重要作用。在这项研究中，我们发现小鼠 LARK (mLARK)（一种 RNA 结合蛋白）可激活小鼠 period1 (mPer1) mRNA 的转录后表达。在视交叉上核中观察到 mLARK 蛋白的强烈昼夜节律周期，其相位与 mPER1 相似，尽管 Lark 转录物的水平没有节律。我们证明 LARK 导致 mPER1 蛋白水平增加，很可能是通过翻译调节，并且 LARK1 蛋白直接与 mPer1 mRNA 3' UTR 中的顺式元件结合。循环细胞中 mLark 表达的改变导致昼夜节律发生显着变化，siRNA 敲低 mLark 导致昼夜节律缩短，而 mLARK1 的过度表达导致昼夜节律延长。这些数据表明 mLARK 是哺乳动物生物钟的新型转录后调节因子。
The mammalian molecular clock is composed of feedback loops to keep circadian 24-h rhythms. Although much focus has been on transcriptional regulation, it is clear that posttranscriptional controls also play important roles in molecular circadian clocks. In this study, we found that mouse LARK (mLARK), an RNA binding protein, activates the posttranscriptional expression of the mouse Period1 (mPer1) mRNA. A strong circadian cycling of the mLARK protein is observed in the suprachiasmatic nuclei with a phase similar to that of mPER1, although the level of the Lark transcripts are not rhythmic. We demonstrate that LARK causes increased mPER1 protein levels, most likely through translational regulation and that the LARK1 protein binds directly to a cis element in the 3' UTR of the mPer1 mRNA. Alterations of mLark expression in cycling cells caused significant changes in circadian period, with mLark knockdown by siRNA resulting in a shorter circadian period, and the overexpression of mLARK1 resulting in a lengthened period. These data indicate that mLARKs are novel posttranscriptional regulators of mammalian circadian clocks.