Barnea E, Bergman Y
The Hubert H. Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University, Hadassah Medical School, Jerusalem 91120, Israel.
J Biol Chem. 2000 Mar 3;275(9):6608-19. doi: 10.1074/jbc.275.9.6608.
The Oct-3/4 transcription factor is expressed in the earliest stages of embryogenesis, and is thus likely to play an important role in regulation of initial decisions in development. For the first time, we have shown that SF1 and Oct-3/4 are co-expressed in embryonal carcinoma (EC) P19 cells, and their expression is down-regulated with very similar kinetics following retinoic acid (RA) induced differentiation of these cells, suggesting a functional relationship between the two. Previously, we have shown that the Oct-3/4 promoter harbors an RA-responsive element, RAREoct, which functions in EC cells as a binding site for positive regulators of transcription, such as RAR and RXR. In this study we have identified in the Oct-3/4 promoter two novel SF1-binding sites: SF1(a) and SF1(b). The proximal site, SF1(a), is located within the RAREoct, and the distal site, SF1(b), is located between nucleotide -193 and -209 of the Oct-3/4 promoter. Both sites contribute to activation of Oct-3/4 promoter in EC cells, with SF1(a) playing a more crucial role. SF1, and its isoforms ELP2 and ELP3 bind to both SF1 sites and activate the Oct-3/4 promoter. This activation depends on the presence of SF1 DNA-binding domain. Thus, Oct-3/4 is the first EC-specific gene reported that is regulated by SF1. Interestingly, SF1 and RAR form a novel complex on the RAREoct sequence that synergistically activate the Oct-3/4 promoter. Both RARE and SF1 cis regulatory elements, as well as the SF1 DNA-binding domain, are needed for this synergism. SF1 and Oct-3/4 transcription factors play a role in the same developmental regulatory cascade.
八聚体转录因子3/4（Oct-3/4）在胚胎发生的最早阶段表达，因此可能在发育过程中初始决定的调控中发挥重要作用。我们首次发现，类固醇生成因子1（SF1）和Oct-3/4在胚胎癌（EC）P19细胞中共表达，并且在视黄酸（RA）诱导这些细胞分化后，它们的表达以非常相似的动力学下调，这表明两者之间存在功能关系。此前，我们已经表明Oct-3/4启动子含有一个RA反应元件RAREoct，它在EC细胞中作为转录正调控因子（如视黄酸受体（RAR）和视黄酸X受体（RXR））的结合位点发挥作用。在本研究中，我们在Oct-3/4启动子中鉴定出两个新的SF1结合位点：SF1(a)和SF1(b)。近端位点SF1(a)位于RAREoct内，远端位点SF1(b)位于Oct-3/4启动子的核苷酸-193和-209之间。这两个位点都有助于激活EC细胞中的Oct-3/4启动子，其中SF1(a)发挥更关键的作用。SF1及其同工型ELP2和ELP3与两个SF1位点结合并激活Oct-3/4启动子。这种激活依赖于SF1 DNA结合结构域的存在。因此，Oct-3/4是第一个报道的受SF1调控的EC特异性基因。有趣的是，SF1和RAR在RAREoct序列上形成一种新型复合物，协同激活Oct-3/4启动子。这种协同作用需要RARE和SF1顺式调控元件以及SF1 DNA结合结构域。SF 和Oct-3/4转录因子在同一发育调控级联中发挥作用。
