C/EBPβ作为LIF的中介维持小鼠胚干细胞于未分化状态(英文)

C/EBPβ SUSTAINS UNDIFFERENTIATED STATE OF MURINE EMBRYONIC STEM CELLS AS A MEDIATOR OF LIF

C/EBPβ(CCAAT/增强子结合蛋白β,又称NF-IL6)是一个多功能的转录因子,其主要功能之一是促进细胞分化。白血病抑制因子(LIF)是一个细胞因子,其在不同类型的细胞中具有不同的效应:它诱导前脂肪细胞分化,却抑制小鼠胚多能干细胞(mES)的分化。在mES中,C/EBPβ究竟起什么作用,尚未有报道。本文首次报告在mES中,在LIF蛋白存在下,C/EBPβ的作用是维持mES的未分化状态,即C/EBPβ是LIF的调控对象。主要事实如下。在mES细胞中,内源C/EBPβ蛋白的表达量与加到培养基中的LIF蛋白的量呈正相关。而在未分化的mES细胞中人工高表达的外源C/EBPβ蛋白和其截短形式LIP蛋白,在LIF存在下,也不但不促进反而抑制mES细胞分化,C/EBPβ的大分子异型蛋白还显著促进mES细胞的增殖;而且,在LIF去除后,这种促进mES细胞增殖的效应还能持续一段短时间。当LIF不存在时,C/EBPβ和LIP才如所预期的那样,诱导分化相关基因表达并促进细胞分化。C/EBPβ和LIP所调控的某些分化相关的基因的表达水平,当LIF存在时,也比没有LIF时显著降低。因此,在mES细胞中C/EBPβ是受LIF的调控而作为LIF的中介,维持mES于未分化状态。

C/EBPβ （also called NF-IL6） is a multifunctional transcription factor, a major function of which is the enhancement of cellular differentiation. Leukemia inhibitory factor （LIF） is a cytokine playing divergent roles in different cell types： induces differentiation in preadipocytes and, however, inhibits differentiation in pluripotent murine embryonic stem （mES） cells. However, roles of C/EBPβ in ruES cells are obscure. Here, we show for the first time that C/EBPβ in the presence of LIF plays a role of sustaining undifferentiated state in this cell line, i.e. C/EBPβ is a target of regulation of LIF, as described as follows. The expression of en.dogenous C/EBPβ proteins in mES cells is positively correlated with the LIF added into medium. Even the exogenous C/EBPβ proteins and their truncated form, LIP, artificially overexpressed in undifferentiated mES cells, do not enhance but inhibit ES cells＇ differentiation in the presence of LIF, and the long isoforms of C/ EBPβ proteins strongly enhance cell propagation. This enhancement lasts for a certain short time even after LIF removal. In the absence of LIF, C/EBPβ and LIP induce expression of differentiation-related genes and promote mES cells＇ differentiation, as anticipated. With LIF, the expression levels of some differentiation-related genes regulated by C/EBPβ and LIP were significantly lower than that without LIF. Therefore, in pluripotent mES tains undifferentiated state of those cells as a mediator cells C/EBPβ is regulated by LIF and susof LIF.