三支研究小組各自獨立在小鼠中發(fā)現(xiàn)一個生理節(jié)奏基因,。誘變篩選（Mutagenesis screens）結(jié)果顯示,，編碼FBXL3蛋白的基因發(fā)生突變，小鼠的生物鐘會延長幾個小時,；生化分析結(jié)果顯示FBXL3是生物鐘關(guān)鍵蛋白的降解所必需的,。文章刊登于兩篇Science文章和一篇Cell文章。
“我覺得這是一個非常令人振奮的發(fā)現(xiàn),，” Scripps 研究所Steve Kay說（未參與研究）,，“說明早期遺傳學(xué)仍舊是鑒別新的鐘基因（clock genes）的有利工具。”
哺乳動物的生理節(jié)奏是由基因轉(zhuǎn)錄和翻譯的反饋環(huán)產(chǎn)生的,。轉(zhuǎn)錄因子CLOCK和BMAL1驅(qū)動鐘基因Period (Per)和Cryptochrome (Cry)表達(dá),，這兩種基因表達(dá)的蛋白與CLOCL和BMAL1相互作用，抑制它們的轉(zhuǎn)錄,。PER和CRY蛋白降解,，抑制作用下降，轉(zhuǎn)錄重新開始,?；芈分杏醒訙―elays），以致整個周期約為24小時,。一個重要的延滯含有PER和CRY蛋白的翻譯后修飾,，決定了這些蛋白降解的時長。
第一篇Science文章講述,，英國Harwell醫(yī)學(xué)研究理事會（MRC）Sofia Godinho和劍橋MRC的Elizabeth Maywood率領(lǐng)的研究小組,，誘導(dǎo)小鼠發(fā)生突變以尋找新的生物鐘基因，結(jié)果發(fā)現(xiàn)一個名為Fbxl3的F-box基因發(fā)生突變會導(dǎo)致小鼠的生理周期延長到27個小時（他們稱之為“after hours”）,。“他們在那些突變動物中發(fā)現(xiàn)了一個顯著現(xiàn)象,，”馬薩諸塞大學(xué)醫(yī)學(xué)院David Weaver說（未參與實驗），“這說明（FBXL3）是一個非常重要的調(diào)解者,。”
英文原文：
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Published Online April 26, 2007
Science DOI: 10.1126/science.1141138
Submitted on February 12, 2007
Accepted on April 18, 2007
The After-Hours Mutant Mouse Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period
Sofia I. H. Godinho 1, Elizabeth S. Maywood 2, Linda Shaw 1, Valter Tucci 1, Alun R. Barnard 1, Luca Busino 3, Michele Pagano 3, Rachel Kendall 1, Mohamed M. Quwailid 1, M. Rosario Romero 1, John O'Neill 2, Johanna E. Chesham 2, Debra Brooker 1, Zuzanna Lalanne 1, Michael H. Hastings 2, Patrick M. Nolan 1*
1 Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
2 MRC Laboratory of Molecular Biology, Neurobiology Division, Hills Road, Cambridge CB2 2QH, UK.
3 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
* To whom correspondence should be addressed.
Patrick M. Nolan , E-mail: [email protected]
By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys358Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected PER2 expression and delayed the rate of CRY protein degradation in PER2::LUCIFERASE tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.
