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哺乳动物细胞的生物钟基因:在组织培养中的实际意义

Clock genes of Mammalian cells: practical implications in tissue culture.

作者信息

Kaeffer Bertrand, Pardini Lissia

机构信息

CRNH de Nantes, Institut National Recherche Agronomique, Unité Fonctions Digestives et Nutrition Humaine, BP 71627 44316, NANTES, Cedex 03, France.

出版信息

In Vitro Cell Dev Biol Anim. 2005 Nov-Dec;41(10):311-20. doi: 10.1007/s11626-005-0001-7.

Abstract

The clock genes family is expressed by all the somatic cells driving central and peripheral circadian rhythms through transcription/translation feedback loops. The circadian clock provides a local time for a cell and a way to integrate the normal environmental changes to smoothly adapt the cellular machinery to new conditions. The central circadian rhythm is retained in primary cultures by neurons of the suprachiasmatic nuclei. The peripheral circadian rhythms of the other somatic cells are progressively dampened down up to loss unless neuronal signals of the central clock are provided for re-entrainment. Under typical culture conditions (obscurity, 37 +/- 1 degrees C, 5-7% CO(2)), freshly explanted peripheral cells harbor chaotic expression of clock genes for 12-14 h and loose, coordinated oscillating patterns of clock components. Cells of normal or cancerous phenotypes established in culture harbor low levels of clock genes idling up to the re-occurrence of new synchronizer signals. Synchronizers are physicochemical cues (like thermic oscillations, short-term exposure to high concentrations of serum or single medium exchange) able to re-induce molecular oscillations of clock genes. The environmental synchronizers are integrated by response elements located in the promoter region of period genes that drive the central oscillator complex (CLOCK:BMAL1 and NPAS2:BMAL1 heterodimers). Only a few cell lines from different species and lineages have been tested for the existence or the functioning of a circadian clockwork. The best characterized cell lines are the immortalized SCN2.2 neurons of rat suprachiasmatic nuclei for the central clock and the Rat-1 fibroblasts or the NIH/3T3 cells for peripheral clocks. Isolation methods of fragile cell phenotypes may benefit from research on the biological clocks to design improved tissue culture media and new bioassays to diagnose pernicious consequences for health of circadian rhythm alterations.

摘要

生物钟基因家族由所有体细胞表达,通过转录/翻译反馈环驱动中枢和外周昼夜节律。生物钟为细胞提供了当地时间,并提供了一种整合正常环境变化的方式,使细胞机制能够顺利适应新环境。初级培养中的中枢昼夜节律由视交叉上核的神经元保留。除非提供中枢生物钟的神经元信号以重新同步,否则其他体细胞的外周昼夜节律会逐渐减弱直至消失。在典型的培养条件下(黑暗、37±1℃、5-7%二氧化碳),新分离的外周细胞在12-14小时内生物钟基因表达混乱,且生物钟成分呈现松散、协调的振荡模式。培养中建立的正常或癌性表型的细胞生物钟基因水平较低,处于闲置状态,直到新的同步信号再次出现。同步器是能够重新诱导生物钟基因分子振荡的物理化学线索(如热振荡、短期暴露于高浓度血清或单次培养基更换)。环境同步器通过位于周期基因启动子区域的反应元件整合,这些元件驱动中枢振荡器复合体(CLOCK:BMAL1和NPAS2:BMAL1异二聚体)。仅对来自不同物种和谱系的少数细胞系进行了昼夜节律机制存在或功能的测试。特征最明确的细胞系是用于中枢生物钟的大鼠视交叉上核永生化SCN2.2神经元,以及用于外周生物钟的大鼠-1成纤维细胞或NIH/3T3细胞。脆弱细胞表型的分离方法可能受益于生物钟研究,以设计改进的组织培养基和新的生物测定法,来诊断昼夜节律改变对健康的有害影响。

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