cPLA2α（cytosolic phospholipase A2 α）是位於細胞內的一種磷脂水解酵素，主要可對細胞膜上phospholipids 的sn-2 位置進行水解，是調節arachidonic aicd 釋放的限制速率酵素。本篇研究中，我們發現在人類肺癌A549 細胞中PKC 的活化劑，phorbol 12-myristate 13-acetate ( PMA )，和proinflammatory cytokine，IL-1β，會增加cPLA2α mRNA 和蛋白質的表現，並呈現time-dependent 現象，但IL-1β和PMA 調節cPLA2α表現之分子機轉似乎不太相同；從報告基因分析顯示PMA 在cPLA2α啟動區的反
應區域在-53 至-35 之間。同時，PMA 造成c-Jun 的活化會誘導cPLA2α啟動區活性增加，且與PMA 的反應區域是相同的。利用DNA affinityprecipitation assay 發現，Sp1 會直接結合至啟動區上非典型的Sp1 位置，而在PMA 刺激之下，核內的Sp1 蛋白結合至啟動區序列上的量不會改變，但c-Jun 的量則會增加，由於在這段啟動區序列上沒有已知的AP1結合位置，所以Sp1 可能扮演carrier 蛋白的角色，在PMA 刺激下會增加與c-Jun 的結合能力，並將之帶到啟動區上驅使cPLA2α基因轉錄活性增加。在IL-1β調控cPLA2α的部分，我們發現IL-1β無法誘導cPLA2α啟動
區活性增加，因此我們認為IL-1β可能是透post -transcriptional 方式來調控。我們發現IL-1β會促使cPLA2α mRNA 的半衰期增加，而在cPLA2α 3’端非轉錄區域中有四個AUUUA 的調控序列，且在物種間有高度保留性；已有文獻指出，這AUUUA 序列post-transcriptional 的調控機轉有關並會造成mRNA 的不穩定；將全長cPLA2α 3’端非轉錄區域插入luciferase報告基因的非轉錄區域會造成luciferase 活性下降80﹪，而IL-1β會稍微回復原本luciferase 活性下降的情形。因此，在本篇研究中，我們認為不同的agonists 可能會經由不同的transcriptional 和post-transcriptional 的過程來調控cPLA2α基因的表現。

　　cPLA2α ( cytosolic phospholipase A2 α) is the major intracellular form ofPLA2, which selectively hydrolyzes membrane phospholipids at the sn-2　position, and the rate-limiting enzyme in the eicosanoid production. In thepresent study, we found that phorbol 12-myristate 13-acetate ( PMA ), anactivator of PKC, and proinflammatory cytokine, IL-1β, increased the expression of cPLA2α mRNA and protein synthesis in a time-dependent manner in A549 cells. But the molecular mechanism was seems different. Reporter assays revealed the PMA response element was in the region of –53 to -35 bp. Furthermore, the promoter activity of cPLA2α gene induced by c-Jun activation was also regulated in the same manner as PMA. By using the DNA affinity precipitation assay in A549 cells, Sp1 directly interacted with the atypical Sp1 site of the promoter and the binding pattern between Sp1 and DNA was not changed between the control and PMA treated cells. However, PMA increased the binding of c-Jun to Sp1. Because there is no typical AP1
binding sequence in this promoter region, Sp1 may act as a carrier protein to bring c-Jun to the promoter to transactivate the transcriptional activity of cPLA2α gene. In the gene regulation of cPLA2α by IL-1β, it failed to induce the promoter activity of cPLA2α gene. But we found that IL-1β increased the half-life of cPLA2α mRNA, indicating a role for post-transcriptional modulation of gene expression. The AU-rich region of the 3’-UTR of cPLA2αis highly conserved across species. Insertion of the entire 3’-UTR of cPLA2α into the 3’-UTR of luciferase resulted in a 80﹪decrease in luciferase activity and IL-1β somewhat recovered the decrease in luciferase activity. In this study, we delineated the contributions of transcriptional and post-transcriptional process to the regulation of cPLA2α gene expression in response to a variety of agonists in A549 cells.

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