Regulatory mechanism of human factor IX gene: protein binding at the Leyden-specific region.
Regulatory mechanism of human factor IX gene: protein binding at the Leyden-specific region.
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人因子 IX 基因的调节机制：Leyden 特异性区域的蛋白质结合。
DOI：
10.1021/bi00172a039
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发表时间：
1994
期刊：
影响因子：
2.9
通讯作者：
Kurachi,K
中科院分区：
文献类型：
--
作者：
Kurachi,S;Furukawa,M;Salier,JP;Wu,CT;Wilson,EJ;French,FS;Kurachi,K
摘要：B-Leyden血友病以青春期发病后出血逐渐改善为特征。迄今为止发现的所有Leyden表型突变都位于Leyden特异性区域，该区域大致跨越人类因子IX基因5'末端的nt-40至+ 20。在HepG2细胞核提取物中，leyden特异性区域及其邻近区域的normalfactor IX基因显示了5个DNase I足迹：FP-I (nt+ 4至+ 19),FP-II (nt-16至3),FP-III (nt-27至19),FP-IV （nt-67至49）和FP-V （nt-99至77）。在这些区域存在Leyden表型突变时，含有FP-I、FP-II或FP-III序列的短寡核苷酸的蛋白质结合亲和力大幅降低，这与这些突变对因子IX基因表达的负面影响密切相关。nt-20 （T到A）的Leyden表型突变导致FP-III和FP-II两个足迹的丢失，但产生了一个新的足迹FP-III'(nt-34到23)，与FP-III部分重叠，表明这些位点存在突变依赖的竞争性蛋白质结合。虽然FP-III‘区含有雄激素响应元件样序列，但结合FP-III’的核蛋白不是雄激素受体。该蛋白不被抗雄激素受体抗体识别，而且不仅存在于肝脏中，而且在电泳迁移转移试验中也存在于雄激素受体阳性和雄激素受体阴性的细胞中。睾酮处理HepG2细胞后，该蛋白的核浓度显著升高。在外源雄激素受体存在时，其与含有FP-III序列的寡核苷酸（-32sub）的结合亲和力大大降低，表明该蛋白可能与雄激素受体相互作用。这种蛋白和一种结合FP-III（可能是HNF-4）到32sub的蛋白在nt-26位点发生突变时的亲和力都大大降低。这些发现表明，青春期后nt-20突变的B-Leyden血友病的改善涉及到在FP-III上结合一个特定的非雄激素受体核蛋白，并且它能够通过在睾酮激增时与雄激素受体的增强相互作用，最佳地替代正常基因中与FP-III结合的蛋白质的功能。人类肝脏中因子IX基因的主要转录起始位点被确定在nt-176，将整个leyden特异性区域定位在5'-未翻译区域。因子IX (FIX) 1在血液凝固的早期和维持中起着至关重要的作用（Hedner & Davie, 1989; Kurachi et al., 1993），体循环缺乏它会导致B型血友病（Briet et al., 1982）。与大多数其他凝血因子一样，FIX基因的表达具有很高的肝脏特异性（Salier et al., 1990）。对其发育调控（Yao et al., 1991）和负责其整体表达的各种结构要素进行了描述（Salier et al., 1990; Jallat et al., 1990）。
Revised Manuscript Received October 5, 1993® abstract: Hemophilia B-Leyden is characterized by the gradual amelioration of bleeding after the onset of puberty. All Leyden phenotype mutations found to date lie within the Leyden-specific region, which spans roughly nt-40 to+ 20 inthe 5'end of the human factor IX gene. With HepG2 cell nuclear extracts, the Leyden-specific region and its immediate neighboring region of the normalfactor IX gene showed five DNase I footprints: FP-I (nt+ 4 to+ 19), FP-II (nt-16 to-3), FP-III (nt-27 to-19), FP-IV (nt-67 to-49), and FP-V (nt-99 to-77). Protein binding affinities of short oligonucleotides containing sequences of FP-I, FP-II, or FP-III were substantially reduced in the presence of Leyden phenotype mutations in these areas, correlating well with the negative effects of these mutations on factor IX gene expression. A Leyden phenotype mutation at nt-20 (T to A) caused a loss of both footprints FP-III and FP-II but generated a new footprint, FP-III'(nt-34 to-23), partially overlapping with FP-III, indicatingmutation-dependent competitive protein binding at these sites. Although the FP-III'area contains an androgen responsive element-like sequence, the nuclear proteinthat binds at FP-III'is not androgenreceptor. The protein was not recognizedby anti-androgen receptor antibody and, furthermore, was present not only in liver but also in both androgen receptor-positive and androgen receptor-negative cells in electrophoretic mobility shift assays. The nuclear concentration of this protein increased significantly upon treatment of the HepG2 cells with testosterone. Its binding affinity to an oligonucleotide (-32sub) containing the FP-III'sequence was greatly reduced in the presence of exogenous androgen receptor, suggesting a possible interaction of this protein with androgen receptor. The affinities of both this protein and a protein which bindsto FP-III (presumably HNF-4) to-32sub with a mutation at nt-26 were grossly lowered. These findings suggest that the amelioration of hemophilia B-Leyden with a mutation at nt-20 afterpuberty involves binding of a specific non-androgen recepter nuclear protein at FP-III'and it is able to substitute for the function of a protein bound at FP-III in the normal gene optimally through its elevated interactionwith androgen receptor upon a surge of testosterone. The major transcriptional initiation site of the factor IX gene in human liver was determined to be at nt-176, localizing the entire Leyden-specific region to the 5'-untranslated region.Factor IX (FIX) 1 plays a crucial role in the early phase and maintenance of blood coagulation (Hedner & Davie, 1989; Kurachi et al., 1993), and itsdeficiency from the systemic circulation results in hemophilia B (Briet et al., 1982). Like most other blood coagulation factors, the FIX gene is expressed with a high liver specificity (Salier et al., 1990). Its developmental regulation (Yao et al., 1991) and various structural elements responsible for its overall expression have been described (Salier et al., 1990; Jallat et al., 1990).
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小鼠因子 IX cDNA 的表征以及肝脏中因子 IX 基因表达的发育调控
影响因子：
6.7
作者：
S. Yao;Audrey DeSilva;S. Kurachi;L. Samuelson;K. Kurachi
通讯作者：
K. Kurachi
DOI：
10.1016/s0021-9258(18)52466-2
发表时间：
1991-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Simental;Madhabananda Sar;Malcolm V. Lane;Frank S. French;E. M. Wilson
通讯作者：
J. Simental;Madhabananda Sar;Malcolm V. Lane;Frank S. French;E. M. Wilson
B 型血友病 Leyden：在 -21 位用胸腺嘧啶取代鸟嘌呤会导致因子 IX 启动子中肝细胞核因子 4 结合位点的破坏。
影响因子：
20.3
作者：
Marlene J. Reijnen;K. Peerlinck;Diedka Maasdam;R. Bertina;Pieter H. Reitsma
通讯作者：
Pieter H. Reitsma
人类因子 IX 基因 5-调节区的功能特征。
DOI：
--
发表时间：
1990
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Salier,JP;Hirosawa,S;Kurachi,K
通讯作者：
Kurachi,K
DOI：
10.1073/pnas.89.14.6300
发表时间：
1992-07-15
影响因子：
11.1
作者：
REIJNEN, MJ;SLADEK, FM;REITSMA, PH
通讯作者：
REITSMA, PH