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Molecular Studies on a Novel Receptor-type Transcription factor, AhR/Arnt.

新型受体型转录因子 AhR/Arnt 的分子研究。

基本信息

批准号：
06454667
负责人：
FUJII Yoshiaki
金额：
$ 3.97万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

When taken up in the cells, environmental pollutants usually represented by 2,3,7,8 tetrachlorodibenzodioxin exert various adverse biologicl effects such as teratogenesis, tumour promotion, immuno-decifiency, and epidermal dysplasia, in addition to induction of drug-metabolizing enzymes. These effects are considered to be mediated by Ah receptor (AhR). we cloned cDNA for AhR and deduced its primary structure from sequence analysis, which turned out to be a receptor-type transcription factor with novel bHLH and PAS domains at its N-terminus. The PAS is designated as a conserved sequence among Drosophila Per, Arnt (Ah receptor nuclear translocator) and Drosophila Sim.Immunochemical analysis revealed that AhR andarnt form a complex to bind the XRE sequence, an inducible enhancer sequence to in response to ducers. The AhR/Arnt complex enhanced in vitro transcription of CYP1A1 gene in cooperation with Sp1, mimicking the transcription of the gene in the DNA transfer experiments. The two transcription factors interacted with each other on their cognate DNA elements to enhance the transcription. cDNA clones of novel members of the b/HLH/PAS family were isolated from cDNA libraries of mouse embryos and their expressions were investigated by the RNA blot hybridization and whole mount in situ hybridization. They were expressed specifically in the limited tissues of the developing embryos, suggesting the functional roles in the development. One of the clones is mSim, a mouse counterpart of the human gene which is suggested to be a causative gene for Down Syndrome.

通常以2，3，7，8四氯二苯并二恶英为代表的环境污染物进入细胞后，除了诱导药物代谢酶外，还具有多种不良生物效应，如致畸、促肿瘤、免疫蜕膜、表皮发育不良等。这些效应被认为是由AH受体(AhR)介导的。我们克隆了AhR的cDNA，并通过序列分析推测了其一级结构，该转录因子是一个受体类型的转录因子，在其N端具有新的bHLH域和PAS结构域。Pas在果蝇Per、ArnT和果蝇SIM3个亚型中被认为是一个保守序列。免疫化学分析表明，AhR和Art形成了一个与XRE序列结合的复合体，XRE序列是一种可诱导的增强子序列。AhR/Arnt复合体与Sp1协同增强细胞色素P1A1基因的体外转录，模拟DNA转移实验中该基因的转录。这两个转录因子在各自的同源DNA元件上相互作用，从而促进转录。从小鼠胚胎c DNA文库中分离到b/hlh/pas家族新成员的cDNA克隆，并用RNA印迹杂交和整体原位杂交方法研究其表达情况。它们在发育中的胚胎有限的组织中特异表达，暗示了它们在发育中的功能作用。其中一个克隆是MSIM，这是一种与人类基因对应的小鼠基因，被认为是唐氏综合症的致病基因。