Thomas George
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
Biol Res. 2002;35(2):305-13. doi: 10.4067/s0716-97602002000200022.
The discussion will focus on the role of the ribosomal protein S6 kinase (S6K) signaling pathway in the regulation of cell growth and proliferation. Although 40S ribosomal protein S6 phosphorylation was first described 25 years ago (Gressner and Wool, 1974), it only recently has been implicated in the translational up-regulation of mRNAs coding for the components of protein synthetic apparatus (Fumagalli and Thomas, 2000). These mRNAs contain an oligopyrimidine tract at their 5' transcriptional start site, termed a 5'TOP, which has been shown to be essential for their regulation at the translational level (Meyuhas et al., 1996). In parallel, a great deal of information has accumulated concerning the identification of the signaling pathway and the regulatory phosphorylation sites involved in controlling S6K activation (Dufner and Thomas, 1999). Despite this knowledge we are only beginning to identify the direct upstream elements involved in growth factor-induced kinase activation (Dennis et al., 2001; Pullen et al., 1998). Use of the immunosuppressant rapamycin, a bacterial macrolide, in conjunction with dominant interfering and activated forms of S6K1 has helped to establish the role of this signaling cascade in the regulation of growth and proliferation (Dennis and Thomas, 2002). In addition, current studies employing the mouse as well as Drosophila melanogaster have provided new insights into physiological function of S6K in the animal (Montagne et al., 1999; Pende et al., 2000). Loss of dS6K function in Drosophila melanogaster demonstrated its paramount importance in development and growth control (Montagne et al., 1999), whereas deletion of the S6K1 gene in the mouse led to an animal of reduced size and the identification of the S6K1 homologue, S6K2 (Shima et al., 1998). Such mice are significantly smaller during fetal development (Shima et al., 1998) and hypoinsulinemic in the adult, conditions known to lead to type 2 diabetes (Pende et al., 2000).
讨论将聚焦于核糖体蛋白S6激酶（S6K）信号通路在细胞生长和增殖调控中的作用。尽管40S核糖体蛋白S6磷酸化在25年前就首次被描述（格雷森纳和伍尔，1974年），但直到最近它才被认为与编码蛋白质合成装置组件的mRNA的翻译上调有关（富马加利和托马斯，2000年）。这些mRNA在其5'转录起始位点含有一个寡嘧啶序列，称为5'TOP，已证明该序列对于它们在翻译水平的调控至关重要（梅尤哈斯等人，1996年）。与此同时，关于识别控制S6K激活的信号通路和调节性磷酸化位点，已经积累了大量信息（杜夫纳和托马斯，1999年）。尽管有这些知识，我们才刚刚开始识别参与生长因子诱导激酶激活的直接上游元件（丹尼斯等人，2001年；普伦等人，1998年）。免疫抑制剂雷帕霉素（一种细菌大环内酯）与显性干扰和激活形式的S6K1联合使用，有助于确立该信号级联在生长和增殖调控中的作用（丹尼斯和托马斯，2002年）。此外，目前以小鼠和黑腹果蝇为实验对象的研究，为S6K在动物体内的生理功能提供了新的见解（蒙塔涅等人，1999年；彭德等人，2000年）。黑腹果蝇中dS6K功能的丧失证明了其在发育和生长控制中的至关重要性（蒙塔涅等人，1999年），而小鼠中S6K1基因的缺失导致动物体型变小，并鉴定出了S6K1的同源物S6K2（岛等人，1998年）。这种小鼠在胎儿发育期间明显较小（岛等人，1998年），成年后胰岛素分泌不足，这些情况已知会导致2型糖尿病（彭德等人，2000年）。
