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首页> 外文学位 >Promoter activity and regulation of human CYP4F2 LTB(4) omega-hydroxylase gene in HEPG2 cells.
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Promoter activity and regulation of human CYP4F2 LTB(4) omega-hydroxylase gene in HEPG2 cells.

机译：HEPG2细胞中人CYP4F2 LTB（4）ω-羟化酶基因的启动子活性和调控。

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摘要

Leukotriene B4 (LTB4) is a potent pro-inflammatory mediator implicated in the pathogenesis of autoimmune inflammatory disease, liver injury and colon cancer. The human CYP4F2 gene encodes a LTB4 o-hydroxylase that metabolizes LTB4 to a biologically less active metabolite. Thus CYP4F2 has an important role in controlling inflammation. Understanding of CYP4F2 gene structure and regulation will provide information on the role of arachidonic acid and LTB4 metabolism in the mechanism underlying the inflammatory process, which may provide alternative avenues for the development of therapeutic drugs in treatment of inflammatory diseases.;The human CYP4F2 gene was isolated and a 6.7 kb (kilobases) 5'end fragment of the gene was sequenced. The CYP4F2 gene is about 20 kb long and contains 13 exons. Primer extension identified that the gene transcription starts at 49 bp (basepairs) upstream the 3' end of exon 1. The CYP4F2 gene has typical basic promoter elements such as TATA and CCAAT boxes, which have not been identified in other CYP4F gene family members. The region between -145bp and -84bp is critical for the promoter activity. An alternative promoter region may exist upstream the ATG codon in exon 2. Regulation studies show that the peroxisome proliferators Wy14,643 and PDFO inhibit CYP4F2 gene transcription. The nuclear receptor cotransfection studies show that hPPARalpha/RXRalpha can further enhance the inhibitory function of Wy14,643 Gene expression is stimulated by 10 muM 9-cis retinoic acid, and is further enhanced by hRXRalpha cotransfection while hRARalpha cotransfection can compromise the hRXRalpha enhancement. A putative Wy14,643 response element is found at the three hexamer repeat DR-1 element at -23 bp. A RARalpha element is identified at -717 bp of the gene, which may inhibit CYP4F2 gene activation mediated by hRXRalpha A 50% inhibition of gene expression is noted following addition of the pro-inflammatory cytokines TNFalpha, IL-6 and IFNgamma (100--200 ng/ml) in transfection assay. These data suggest a link between peroxisome proliferators, retinoic acids and inflammation control, and help us to further understand the role of CYP4F2 gene in inflammation, lipid homeostasis and carcinogenesis.
机译：白三烯B4（LTB4）是有效的促炎介质，与自身免疫性炎性疾病，肝损伤和结肠癌的发病机理有关。人CYP4F2基因编码LTB4 o-羟化酶，该酶将LTB4代谢为生物活性较低的代谢物。因此CYP4F2在控制炎症中具有重要作用。对CYP4F2基因结构和调控的了解将提供有关花生四烯酸和LTB4代谢在炎症过程潜在机制中的作用的信息，这可能为开发用于治疗炎症性疾病的治疗药物提供替代途径。分离，并对该基因的6.7kb（千碱基）的5'末端片段进行测序。 CYP4F2基因长约20 kb，含有13个外显子。引物延伸确定基因转录起始于外显子1 3'端上游49 bp（碱基对）。CYP4F2基因具有典型的基本启动子元件，例如TATA和CCAAT盒，在其他CYP4F基因家族成员中尚未发现。 -145bp和-84bp之间的区域对于启动子活性至关重要。一个外显子2的ATG密码子上游可能存在一个替代启动子区域。调控研究表明，过氧化物酶体增殖物Wy14,643和PDFO抑制CYP4F2基因的转录。核受体共转染研究表明，hPPARalpha / RXRalpha可以进一步增强Wy14,643的抑制功能，而10μM9-顺式视黄酸会刺激基因表达，而hRXRalpha共转染会进一步增强其表达，而hRARalpha共转染会损害hRXRalpha的增强。在三个六聚体重复DR-1元件的-23 bp处发现了一个假定的Wy14,643响应元件。在该基因的-717 bp处鉴定到一个RARalpha元件，该元件可能抑制hRXRalpha介导的CYP4F2基因激活。在添加促炎细胞因子TNFalpha，IL-6和IFNgamma后，注意到基因表达受到50％的抑制（100-- 200 ng / ml）。这些数据表明过氧化物酶体增殖物，视黄酸和炎症控制之间存在联系，并帮助我们进一步了解CYP4F2基因在炎症，脂质稳态和致癌作用中的作用。

著录项

  • 作者

    Zhang, Xiaolan.;

  • 作者单位

    Kent State University.;

  • 授予单位 Kent State University.;
  • 学科 Molecular biology.;Genetics.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 241 p.
  • 总页数 241
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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