Allelic variation of the MMP3 promoter affects transcription activity through the transcription factor C-MYB in human brain arteriovenous malformations.
Allelic variation of the MMP3 promoter affects transcription activity through the transcription factor C-MYB in human brain arteriovenous malformations.
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MMP3 启动子的等位基因变异通过转录因子 C-MYB 在人脑动静脉畸形中影响转录活性
DOI：
10.1371/journal.pone.0057958
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Huai C;Song J;Ma Z;Qin X;Li P;Chen H;Zhao F;Lu D;Song D;Mao Y;Song X;Zhao Y
MMPs包括降解细胞周围物质的蛋白水解酶家族，其可导致血管不稳定并与脑动静脉畸形（BAVM）的发展相关。MMP 3是该家族的关键成员，在BAVM组织中过表达，并且MMP 3内的单核苷酸多态性，− 709 A>G（rs 522616）与BAVM的风险显著相关。本研究旨在探讨rs 522616多态性调控MMP 3表达的机制。我们的结果表明，与G等位基因相比，− 709 A导致超过2倍的转录活性（P<0.05），并且这种转录活性可以通过与含有− 709 A但不含− 709 G的竞争性DNA片段共转染细胞来抑制。生物信息学分析表明，转录因子C-MYB可能与rs 522616附近区域结合。在HEK 293和HUVEC细胞中，与− 709 G或不过表达c-myb的对照相比，过表达c-myb显著增加了− 709 A的转录活性（P<0.01）。ChIP分析表明，C-MYB结合到两个细胞系和三个BAVM组织样品中的SNP区域。总之，这些数据表明C-MYB可以结合MMP 3启动子的− 709 A等位基因，激活其转录并导致该基因的更高表达。这一新的假说得到了分子证据的支持，解释了这种SNP如何影响MMP 3启动子功能并导致BAVM发展的风险。
MMPs comprise a family of proteolytic enzymes that degrade pericellular substances, which may result in the destabilization of vessels and related to the development of brain arteriovenous malformations (BAVM). MMP3 is a key member of this family, overexpressed in BAVM tissues, and a single nucleotide polymorphism within MMP3, −709A>G (rs522616), is significantly associated with the risk of BAVM. In this study, we aimed to investigate the mechanism through which the polymorphism rs522616 regulates the expression of MMP3. Our results showed that −709A led to a over 2-fold higher transcriptional activity compared with the G allele (P<0.05) and this transcriptional activity can be depressed by co-transfecting cells with competitive DNA fragments containing −709A but not −709G. Bioinformatics analyses suggested that the transcription factor C-MYB might bind to the area around rs522616. Overexpressed C-MYB significantly increased the transcriptional activity of −709A compared with −709G or controls that did not overexpress c-myb (P<0.01) in HEK293 and HUVEC cells. ChIP assays indicated that C-MYB bound to the SNP region in the two cell lines and three BAVM tissue samples. Together, these data indicated that C-MYB can bind to the −709A allele of the MMP3 promoter, activate its transcription and lead to a higher expression of this gene. This novel hypothesis, supported by molecular evidence, explains how this SNP affects MMP3 promoter function and results in a risk of BAVM development.
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大脑血管畸形的生物学。
影响因子：
8.3
作者：
Leblanc GG;Golanov E;Awad IA;Young WL;Biology of Vascular Malformations of the Brain NINDS Workshop Collaborators
通讯作者：
Biology of Vascular Malformations of the Brain NINDS Workshop Collaborators
影响因子：
3.5
作者：
Luo, J
通讯作者：
Luo, J
影响因子：
4.6
作者：
Dey, Sanjib;Stalin, Sami;Swarnakar, Snehasikta
通讯作者：
Swarnakar, Snehasikta
影响因子：
1.9
作者：
Quick, CM;Hashimoto, T;Young, WL
通讯作者：
Young, WL
影响因子：
4.5
作者：
Johnatty SE;Beesley J;Chen X;Macgregor S;Duffy DL;Spurdle AB;deFazio A;Gava N;Webb PM;Rossing MA;Doherty JA;Goodman MT;Lurie G;Thompson PJ;Wilkens LR;Ness RB;Moysich KB;Chang-Claude J;Wang-Gohrke S;Cramer DW;Terry KL;Hankinson SE;Tworoger SS;Garcia-Closas M;Yang H;Lissowska J;Chanock SJ;Pharoah PD;Song H;Whitemore AS;Pearce CL;Stram DO;Wu AH;Pike MC;Gayther SA;Ramus SJ;Menon U;Gentry-Maharaj A;Anton-Culver H;Ziogas A;Hogdall E;Kjaer SK;Hogdall C;Berchuck A;Schildkraut JM;Iversen ES;Moorman PG;Phelan CM;Sellers TA;Cunningham JM;Vierkant RA;Rider DN;Goode EL;Haviv I;Chenevix-Trench G;Ovarian Cancer Association Consortium;Australian Ovarian Cancer Study Group;Australian Cancer Study (Ovarian Cancer)
通讯作者：
Australian Cancer Study (Ovarian Cancer)