Identification of functional DNA variants in the constitutive promoter region of MDM2.
Identification of functional DNA variants in the constitutive promoter region of MDM2.
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MDM2组成型启动子区域中功能性DNA变异的鉴定。
DOI：
10.1186/1479-7364-6-15
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发表时间：
2012-09-01
期刊：
影响因子：
4.5
通讯作者：
Sinnett D
中科院分区：
文献类型：
--
作者：
Lalonde ME;Ouimet M;Larivière M;Kritikou EA;Sinnett D
尽管癌蛋白小鼠双微体2（MDM 2）的突变很罕见，但在几种人类肿瘤中观察到MDM 2基因过表达。考虑到MDM 2水平的轻微变化可能影响p53肿瘤抑制信号通路，我们推测MDM 2启动子区的序列变异可能导致基因剂量的表达失调和变异。已经报道了MDM 2的两个启动子;内部启动子（P2），其位于内含子1的末端附近并且是p53响应性的，以及上游组成型启动子（P1），其是p53非依赖性的。两个启动子区域都含有可以影响MDM 2表达水平的DNA变体，包括充分研究的单核苷酸多态性（SNP）SNP 309，其位于启动子P2中;即，外显子2的上游。在这份报告中，我们筛选了启动子P1的DNA变体，并评估了相应的SNP的功能影响。使用dbSNP数据库和欧洲血统个体的基因分型验证，我们确定了三种常见的SNP（−1494 G > A; indel 40 bp;和−182 C > G）。通过使用这三个启动子SNP连同rs 2279744（SNP 309）推断三个主要启动子单倍型。亚克隆到一个基因报告系统，我们发现，两个单倍型显着影响MDM 2启动子活性的单倍型特异性的方式。定点诱变实验表明，40 bp的插入/缺失变异引起观察到的等位基因启动子活性。这项研究表明，MDM 2表达水平的变异性的一部分可以解释等位基因p53-独立的P1启动子活性。
Although mutations in the oncoprotein murine double minute 2 (MDM2) are rare, MDM2 gene overexpression has been observed in several human tumors. Given that even modest changes in MDM2 levels might influence the p53 tumor suppressor signaling pathway, we postulated that sequence variation in the promoter region of MDM2 could lead to disregulated expression and variation in gene dosage. Two promoters have been reported for MDM2; an internal promoter (P2), which is located near the end of intron 1 and is p53-responsive, and an upstream constitutive promoter (P1), which is p53-independent. Both promoter regions contain DNA variants that could influence the expression levels of MDM2, including the well-studied single nucleotide polymorphism (SNP) SNP309, which is located in the promoter P2; i.e., upstream of exon 2. In this report, we screened the promoter P1 for DNA variants and assessed the functional impact of the corresponding SNPs. Using the dbSNP database and genotyping validation in individuals of European descent, we identified three common SNPs (−1494 G > A; indel 40 bp; and −182 C > G). Three major promoter haplotypes were inferred by using these three promoter SNPs together with rs2279744 (SNP309). Following subcloning into a gene reporter system, we found that two of the haplotypes significantly influenced MDM2 promoter activity in a haplotype-specific manner. Site-directed mutagenesis experiments indicated that the 40 bp insertion/deletion variation is causing the observed allelic promoter activity. This study suggests that part of the variability in the MDM2 expression levels could be explained by allelic p53-independent P1 promoter activity.
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DOI：
10.1159/000134368
发表时间：
1996-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
Meddeb, M;Valent, A;Bernheim, A
通讯作者：
Bernheim, A
影响因子：
11.5
作者：
Dharel, Narayan;Kato, Naoya;Omata, Masao
通讯作者：
Omata, Masao
影响因子：
64.5
作者：
Bond, GL;Hu, WW;Levine, AJ
通讯作者：
Levine, AJ
影响因子：
2.3
作者：
Hol, SY;Wang, YJ;Guo, HR
通讯作者：
Guo, HR
影响因子：
11.2
作者：
Hu, Wenwei;Feng, Zhaohui;Levine, Arnold J.
通讯作者：
Levine, Arnold J.