INTERACTION OF NUCLEAR PROTEINS WITH AN AP-1 CRE-LIKE PROMOTER SEQUENCE IN THE HUMAN TNF-ALPHA GENE
INTERACTION OF NUCLEAR PROTEINS WITH AN AP-1 CRE-LIKE PROMOTER SEQUENCE IN THE HUMAN TNF-ALPHA GENE
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DOI：
10.1002/jlb.56.1.27
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发表时间：
1994-07-01
影响因子：
5.5
通讯作者：
LOPEZBERESTEIN, G
中科院分区：
文献类型：
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作者：
NEWELL, CL;DEISSEROTH, AB;LOPEZBERESTEIN, G
肿瘤坏死因子α启动子含有AP-1/Cre样结合位点TGAGCTCA。AP-1元件一般转导涉及蛋白激酶C的信号；Cre位点介导cAMP反应，涉及蛋白激酶A。因此，该元件具有通过不同的信号通路接收信号的潜力。用分别刺激THP-1单核细胞的脂多糖(LPS)、地塞米松(Dex)或己酮可可碱(PTX)处理的THP-1单核细胞提取物与核蛋白结合的研究表明，两个低迁移率的复合体可能通过这个启动子区域参与调节。与未经处理的细胞相比，PTX和Dex增加了这两个复合体的结合；大约在内毒素诱导2小时后，上层复合体变得不可检测到。这个上层复合体由ATF2(激活转录因子2，一种环状AMP反应元件结合蛋白)同源二聚体组成；下层是Jun/ATF2的异源二聚体。脂多糖可诱导c-jun，从而促进Jun/ATF2复合体的形成，从而激活复合体。在这种情况下，在地塞米松或PTX存在的情况下同时存在这两种复合体，可以通过竞争结合减少肿瘤坏死因子的转录数量。通过体外竞争性结合研究比较肿瘤坏死因子启动子序列和共识Cre的结合亲和力，我们进一步提出内源结合序列与共识结合序列的差异可能是调控特定基因的重要特性。
The tumor necrosis factor alpha (TNF-alpha) promoter contains an AP-1/CRE-like binding site, TGAGCTCA. AP-1 elements generally transduce signals involving protein kinase C; the CRE site mediates a cAMP response, involving protein kinase A. Thus, this element has the potential to receive signals through divergent signaling pathways. Nuclear protein binding studies using extracts from THP-1 monocytic cells treated with lipopolysaccharide (LPS), which stimulates, or dexamethasone (Dex) or pentoxifylline (PTX), which inhibit TNF production, respectively, suggest that two low-mobility complexes could be involved in regulation through this promoter region. PTX and Dex increase binding of both these complexes compared with untreated cells; approximately 2 hours after LPS induction, the upper complex becomes undetectable. This upper complex is composed of ATF2 (activating transcription factor 2, a cyclic AMP responsive element binding protein) homodimers; the lower is a heterodimer of jun/ATF2. LPS induces c-jun and thus may enhance formation of jun/ATF2 complexes, which could be activating complexes. In this case, the simultaneous presence of both complexes, which would occur in the presence of Dex or PTX, could reduce the amount of TNF transcription through competitive binding. Through is vitro competitive binding studies comparing the binding affinities of the TNF promoter sequence and a consensus CRE, we further suggest how variation of endogenous binding sequences from consensus may be an important property for regulatory control of particular genes.