生物谷報道：以往科學(xué)家對晝夜節(jié)律進行了大量的研究，發(fā)現(xiàn)了晝夜節(jié)律實際上一個復(fù)雜的基因調(diào)控系統(tǒng),，包括clock, per, time等一系列基因相互作用的結(jié)果,。
在本期Cell上封面文章報道了美國西北大學(xué)霍華德休斯醫(yī)學(xué)研究所（Howard Hughes Medical Institute）Joseph S. Takahashi教授的最新發(fā)現(xiàn),，通過ENU（生物谷注：一種可以廣泛導(dǎo)致基因隨機突變的藥物）使小鼠基因隨機突變,，從其中篩選出一種晝夜節(jié)律在26小時左右的晝夜節(jié)律突變型小鼠，稱之為“超時小鼠”,，同時篩選出陽性克隆,，并進行了遺傳學(xué)深入分析。實際上這種超時小鼠的原因在于F-box蛋白FBXL3上一個位點出現(xiàn)突變,，使第364個氨基酸編碼從異亮氨基酸改變成蘇氨酸,，從而使該蛋白失去功能。在這種小鼠上,，Period基因表達的兩種蛋白PER1和PER2都下降了,，然而CRY基因表達的CRY1和CRY2沒有改變,。但是，F(xiàn)BXL3功能的丟失,，使CRY蛋白更穩(wěn)定,，這導(dǎo)致了Per和Cry基因整體轉(zhuǎn)錄的抑制，從而出現(xiàn)了晝夜節(jié)律的延長,。這也表明,，F(xiàn)BXL3是導(dǎo)致晝夜節(jié)律延長的主要因素。
英文摘要：
Using a forward genetics ENU mutagenesis screen for recessive mutations that affect circadian rhythmicity in the mouse, we isolated a long period (26 hr) circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3, a component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss of function in FBXL3, which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and Cry genes. Thus, Fbxl3Ovtm defines a molecular link between CRY turnover and CLOCK/BMAL1-dependent circadian transcription to modulate circadian period.
原始出處：
Circadian Mutant Overtime Reveals F-box Protein FBXL3 Regulation of Cryptochrome and Period Gene Expression.Sandra M. Siepka1, 2, 5, Seung-Hee Yoo2, 5, Junghea Park2, Weimin Song1, Vivek Kumar1, 2, Yinin Hu2, Choogon Lee4 and Joseph S. Takahashi. Cell, Volume 129, Issue 5, 1 June 2007, Pages 1011-1023
