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首页> 外文期刊>Molecular and Cellular Biology >FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression.
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FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression.

机译：FER-1是铁蛋白H基因的增强子，也是E1A介导的转录抑制的靶标。

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Ferritin, the major intracellular iron storage protein of eucaryotic cells, is regulated during inflammation and malignancy. We previously reported that transcription of the H subunit of ferritin (ferritin H) is negatively regulated by the adenovirus E1A oncogene in mouse NIH 3T3 fibroblasts (Y. Tsuji, E. Kwak, T. Saika, S. V. Torti, and F. M. Torti, J. Biol. Chem. 268:7270-7275, 1993). To elucidate the mechanism of transcriptional repression of the ferritin H gene by E1A, a series of deletions in the 5' flanking region of the mouse ferritin H gene were constructed, fused to the chloramphenicol acetyltransferase (CAT) gene, and transiently cotransfected into NIH 3T3 cells with an E1A expression plasmid. The results indicate that the E1A-responsive region is located approximately 4.1 kb 5' to the transcription initiation site of the ferritin H gene. Further analyses revealed that a 37-bp region, termed FER-1, is the target of E1A-mediated repression. This region also serves as an enhancer, augmenting ferritin H transcription independently of position and orientation. FER-1 was dissected into two component elements, i.e., a 22-bp dyad symmetry element and a 7-bp AP1-like sequence. Insertion of these DNA sequences into a ferritin H-CAT chimeric gene lacking an E1A-responsive region indicated that (i) the 22-bp dyad symmetry sequence by itself has no enhancer activity, (ii) the AP1-like sequence has moderate enhancer activity which is repressed by E1A, and (iii) the combination of the dyad symmetry element and the AP1-like sequence is required for maximal enhancer activity and repression by E1A. Gel retardation assays and cotransfection experiments with c-fos and c-jun expression vectors suggested that members of the Fos and Jun families bind to the AP1-like element of FER-1 and contribute to its regulation. In addition, gel retardation assays showed that E1A reduces the ability of nuclear proteins to bind to the AP1-like sequence without affecting the levels of nuclear factors that recognize the 22-bp dyad symmetry element. Taken together, these results demonstrate that FER-1 serves as both an enhancer of ferritin H transcription and a target for E1A-mediated repression.
机译：铁蛋白是真核细胞的主要细胞内铁储存蛋白，在炎症和恶性肿瘤过程中受到调节。我们先前曾报道过，小鼠NIH 3T3成纤维细胞（Y. Tsuji，E. Kwak，T.Saika，SV Torti，and FM Torti，J.）中的腺病毒E1A癌基因对铁蛋白H亚基（ferritin H）的转录负调控。 Biol.Chem.268：7270-7275，1993）。为了阐明E1A抑制铁蛋白H基因转录的机制，在小鼠铁蛋白H基因5'侧翼区域构建了一系列缺失，与氯霉素乙酰基转移酶（CAT）基因融合，并瞬时共转染到NIH 3T3中具有E1A表达质粒的细胞。结果表明，E1A响应区位于铁蛋白H基因转录起始位点约4.1kb 5′处。进一步的分析表明，称为FER-1的37 bp区域是E1A介导的阻遏的目标。该区域还充当增强子，独立于位置和方向来增强铁蛋白H转录。 FER-1被分解成两个组成元件，即一个22bp的二元对称元件和一个7bp的AP1样序列。将这些DNA序列插入缺乏E1A响应区的铁蛋白H-CAT嵌合基因表明（i）22 bp dyad对称序列本身没有增强子活性，（ii）类AP1序列具有中等增强子活性（iii）dyad对称元件和类AP1序列的组合是最大增强子活性和E1A抑制所必需的。凝胶阻滞分析和使用c-fos和c-jun表达载体的共转染实验表明，Fos和Jun家族的成员与FER-1的AP1样元件结合并有助于其调节。此外，凝胶阻滞分析表明，E1A降低了核蛋白与AP1样序列结合的能力，而不会影响识别22 bp dyad对称元件的核因子的水平。综上所述，这些结果表明FER-1既是铁蛋白H转录的增强剂，又是E1A介导的阻遏的靶标。

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