Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein

被引:220
作者
Yagita, K
Tamanini, F
Yasuda, M
Hoeijmakers, JHJ
van der Horst, GTJ
Okamura, H [1 ]
机构
[1] Kobe Univ, Div Mol Brain Sci, Dept Brain Sci, Grad Sch Med, Kobe, Hyogo 6500017, Japan
[2] Erasmus Univ, Dept Cell Biol & Genet, MGC, NL-3000 DR Rotterdam, Netherlands
关键词
circadian clock; cryptochrome; nuclear-cytoplasmic shuttling; period; ubiquitylation;
D O I
10.1093/emboj/21.6.1301
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The core oscillator generating circadian rhythms in eukaryotes is composed of transcription-translation-based autoregulatory feedback loops in which clock gene products negatively affect their own expression. A key step in this mechanism involves the periodic nuclear accumulation of clock proteins following their mRNA rhythms after similar to6 h delay. Nuclear accumulation of mPER2 is promoted by mCRY proteins. Here, using COS7 cells and mCry1/mCry2 double mutant mouse embryonic fibroblasts transiently expressing GFP-tagged (mutant) mPER2, we show that the protein shuttles between nucleus and cytoplasm using functional nuclear localization and nuclear export sequences. Moreover, we provide evidence that mCRY proteins prevent ubiquitylation of mPER2 and subsequent degradation of the latter protein by the proteasome system. Interestingly, mPER2 in turn prevents ubiquitylation and degradation of mCRY proteins. On the basis of these data we propose a model in which shuttling mPER2 is ubiquitylated and degraded by the proteasome unless it is retained in the nucleus by mCRY proteins.
引用
收藏
页码:1301 / 1314
页数:14
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