https://scholars.lib.ntu.edu.tw/handle/123456789/159904
Title: | C/EBPb在由脂多醣引發的間白素-6基因轉錄調控的角色
與活化機制的探討 C/EBPb isoforms and their activity regulation by redox switch in lipopolysaccharide-inducible expression of Interleukin-6 gene |
Authors: | 蘇文琪 Su, Wen-Chi |
Keywords: | 脂多醣 間白素-6 基因轉錄調控;C/EBPb isoforms redox lipopolysaccharide Interleuk | Issue Date: | 2004 | Abstract: | 在發炎反應所誘發基因表現中,C/EBPβ是參與轉錄調控的重要因子之一。NF-κB 是另一個大家熟知,控制發炎細胞激素基因表現的主要因子。這兩個蛋白質均能在轉錄層級上協同地調控IL-6基因的表現。然而,正確調控IL-6基因表現的機制仍待釐清。本論文利用NF-κB抑制劑或減弱C/EBPβ內生性的表現量,我們證實這兩個蛋白質可能在IL-6基因調控上,會隨著細胞的差異而有不同的角色。在LPS的刺激下,NF-κB在RAW264.7細胞中扮演主要活化IL-6基因的角色,但在P388D1(IL1)細胞中,C/EBPβ則顯的較為重要。 C/EBPβ有三個isoforms,其中有兩個是轉錄活化因子(LAP* 和LAP),有一個是轉錄抑制因子(LIP)。我們除了說明C/EBPβ在誘發IL-6基因表現的角色;我們還提供證據支持細胞中的氧化還原狀態可能會控制其中一個C/EBPβisoform (LAP*)的轉錄活性。在還原狀態下,LAP*的DNA結合能力和轉錄活性可被引發。LAP*第11個氨基酸(即半胱氨酸)可能的功能是作為氧化還原狀態的分子探針並調控LAP*活化它的標的基因。C/EBPβ另兩個isoforms :LAP和LIP,由於各別缺少前21和151個氨基酸而不能經由相似的氧化還原法來調節。總結我們所發現的證據提供在P388D1(IL1)細胞裡,主要是由C/EBPβ其中一個isoform: LAP*經氧化還原轉換來調控由LPS所誘 發的IL-6基因表現。 C/EBPb is one of the key transcription factors responsible for the induction of genes involved in inflammatory response. NF-kB is another well-known crucial factor essential for controlling inflammatory cytokine genes expression. These two proteins have been reported to regulate IL-6 gene expression synergistically at the transcription level. However, the exact mechanism through which IL-6 expression is regulated remains uncharacterized. By treating cells with specific inhibitors of NF-kB or knock down the endogenous level of C/EBPb, we have demonstrated that these two proteins may have regulatory roles in IL-6 gene induction during inflammation in cell type-specific manner. In RAW264.7 cells, NF-kB plays predominant roles in activating IL-6 gene upon treatment with LPS while in p388D1(IL1) cells, C/EBPb is apparently more important than NF-kB. C/EBPb has three isoforms, including two transcription activators (LAP* and LAP) and one transcription repressor (LIP). In addition to demonstrating the role of C/EBPb in IL-6 gene induction, we provide evidence that the transcriptional activities of one of the C/EBPb isoforms, LAP*, may be governed by the redox state of the cell. The DNA binding activity and transcriptional activation of LAP* are induced under reducing condition. The 11th amino acid (Cys-11) of LAP* may function as a molecular sensor of redox state that regulates the activity of LAP* toward activating its target genes. The LAP and LIP isoforms of C/EBPb, lacking 21 and 151 amino acids, respectively, are not modulated in a similar redox-responsive manner. Taken together, our observations provide evidence that LAP* is the primary isoform of C/EBPb that regulates, through a redox switch, the LPS-induced expression of the IL-6 gene in P388D1 cells. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/51375 | Other Identifiers: | en-US |
Appears in Collections: | 分子醫學研究所 |
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