Molecular pathology for down-regulation of erythroid-specific genes in prion diseases

朊病毒疾病中红细胞特异性基因下调的分子病理学

基本信息

  • 批准号:
    16208030
  • 负责人:
  • 金额:
    $ 32.2万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
  • 财政年份:
    2004
  • 资助国家:
    日本
  • 起止时间:
    2004 至 2006
  • 项目状态:
    已结题

项目摘要

AHSP is an erythroid-specific molecular chaperone that stabilizes newly synthesised a-globin. Previous studies demonstrated that mRNA levels of AHSP were specifically reduced in hematopoietic tissues of prion-infected animals. The purpose of the present study is to clarify the mechanism for down-regulation of AHSP transcription. A series of truncation and mutation analyses on 2.5-kb 5' upstream region of the AHSP gene in MELhide8 cells and electrophoretic mobility shift assay showed that the minimal 5'-promoter region located at-328-286 to the translation initiation site including a GATA binding motif. Either of two upstream GATA elements at-403 and-381 enhanced reporter gene transcription only in the presence of the minimal GATA element described above. These findings indicate that an erythroid-specific transcription factor GATA-1 is essential to AHSP gene expression and suggest that the down-regulation of AHSP involves changes in GATA-1 transcriptional activation. There was no significant change in gene expression of AHSP, a-globin, b-globin, GATA-1, EKLF, and NF-E2 in MELhide8 cells when the cells were incubated with brain homogenates from scrapie-infected mice for up to 120 hours. Moreover, MELhide8 cells exhibited no accumulation of PrPsc even after 16 passages. These data demonstrated that Prrc has no direct effect on AHSP gene expression in erythroid cells. Instead, IL-6 significantly and IL-1β weakly reduced the expression of AHSP mRNA levels and the AHSP promoter-reporter gene expression in MELhide8 cells in a dose-dependent manner. The reduction was recovered in the presence of the inhibitor of the STAT3 pathway, suggesting that the signal transduction of an inflammatory cytokine IL-6 through STAT3 pathway would modulate GATA-1/AHSP promoter interaction and subsequently causes down-regulation of the AHSP gene.
α-血红蛋白稳定蛋白是一种红系特异性分子伴侣,可稳定新合成的α-珠蛋白。先前的研究表明,α-血红蛋白稳定蛋白的mRNA水平在朊病毒感染动物的造血组织中特异性降低。本研究的目的是阐明α血红蛋白稳定蛋白转录下调的机制。对MELhide 8细胞α-血红蛋白稳定蛋白基因5'端上游2.5kb序列的一系列截短和突变分析及电泳迁移率变动分析表明,最小的5'端启动子区位于翻译起始位点的-328-286位,包含一个加塔结合基序。在-403和-381处的两个上游加塔元件中的任一个仅在上述最小加塔元件存在下增强报告基因转录。这些发现表明红系特异性转录因子加塔-1对α-血红蛋白稳定蛋白基因表达是必需的,并提示α-血红蛋白稳定蛋白的下调涉及加塔-1转录激活的变化。当MELhide 8细胞与羊瘙痒病感染小鼠的脑匀浆孵育120小时时,其α-血红蛋白稳定蛋白、α-珠蛋白、β-珠蛋白、加塔-1、EKLF和NF-E2的基因表达没有显著变化。此外,MELhide 8细胞甚至在16代后也没有显示出PrPsc的积累。这些数据表明Prrc对红系细胞中α-血红蛋白稳定蛋白基因表达没有直接影响。相反,IL-6和IL-1β以剂量依赖性方式显著降低MELhide 8细胞中α-血红蛋白稳定蛋白mRNA水平和α-血红蛋白稳定蛋白启动子-报告基因表达。在STAT 3通路抑制剂的存在下,这种降低被恢复,这表明通过STAT 3通路的炎性细胞因子IL-6的信号转导将调节加塔-1/α-血红蛋白稳定蛋白启动子的相互作用,并随后导致α-血红蛋白稳定蛋白基因的下调。

项目成果

期刊论文数量(23)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle
  • DOI:
    10.1242/jcs.03101
  • 发表时间:
    2006-09-01
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Ito, Daisuke;Koshino, Ichiro;Inaba, Mutsumi
  • 通讯作者:
    Inaba, Mutsumi
Defective membrane expression of anion exchanger 1 (AE1) caused by mutations at the conserved sequence EL(K/Q)(L.C)LD(A/G)DD in the C-terminal tail in HEK293 cells
HEK293 细胞 C 端尾部保守序列 EL(K/Q)(L.C)LD(A/G)DD 突变导致阴离子交换器 1 (AE1) 膜表达缺陷
Inhibition of PrPSc formation by synthetic 0-sulfated glycopyranosides and their polymers.
合成 0-硫酸化吡喃糖苷及其聚合物抑制 PrPSc 形成。
Genetic diagnosis of claudin-16 deficiency and sex determination in bovine preimplantation embryos.
牛植入前胚胎中claudin-16缺陷的基因诊断和性别决定。
Identification of a piroplasm protein of Theileria arientalis that binds to bovine erythrocyte band 3.
鉴定与牛红细胞带 3 结合的东方泰勒虫梨浆蛋白。
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INABA Mutsumi其他文献

INABA Mutsumi的其他文献

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{{ truncateString('INABA Mutsumi', 18)}}的其他基金

TRIM-SUMO-11S proteasome pathway: a possible axis for ubiquitylation-independent endoplasmic reticulum-associated degradation of AE1 mutants
TRIM-SUMO-11S 蛋白酶体途径:AE1 突变体的泛素化独立内质网相关降解的可能轴
  • 批准号:
    16H05031
  • 财政年份:
    2016
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Regulation of erythroblast maturation by TSPO2 through cholesterol accumulation in the endoplasmic reticulum
TSPO2 通过内质网中胆固醇积累调节红细胞成熟
  • 批准号:
    15K14861
  • 财政年份:
    2015
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Roles of pseudo-rhomboid protein Derlins in the Ub-independent ER-associated degradation of membrane proteins
伪菱形蛋白 Derlins 在不依赖于 Ub 的 ER 相关膜蛋白降解中的作用
  • 批准号:
    25292177
  • 财政年份:
    2013
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
A possible mechanism for PrP^<Sc> formation through modification with a lipid peroxidation product hydroxylnonenal at the membrane interface
通过在膜界面处用脂质过氧化产物羟基壬烯醛进行修饰,形成 PrP^<Sc> 的可能机制
  • 批准号:
    22658095
  • 财政年份:
    2010
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
From the ER to the plasma membrane : Vesicular transport of membrane skeleton units and the diseases
从内质网到质膜:膜骨架单元的囊泡运输和疾病
  • 批准号:
    19208027
  • 财政年份:
    2007
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Molecular mechanisms for the assembly of the red cell membrane skeleton during erythroid cell development
红细胞发育过程中红细胞膜骨架组装的分子机制
  • 批准号:
    14360187
  • 财政年份:
    2002
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Analysis for putative relationship between causative genes for hereditary disorder and quantitative traits loci in cattle
牛遗传性疾病致病基因与数量性状位点之间的推定关系分析
  • 批准号:
    13556044
  • 财政年份:
    2001
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular mechanism for the assembly of red cell membrane skeletons based on pathobiology of congenital hemolytic anemia in cattle
基于牛先天性溶血性贫血病理学的红细胞膜骨架组装分子机制
  • 批准号:
    12460137
  • 财政年份:
    2000
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Applications of Tissue-specific Transcription Factor in Animal Gene Therapy
组织特异性转录因子在动物基因治疗中的应用
  • 批准号:
    10556071
  • 财政年份:
    1998
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Molecular and Biochemical Studies on Compensatory Mechanisms for Total Band 3 Deficiency in Japanese Black Cattle
日本黑牛总带 3 缺陷补偿机制的分子和生化研究
  • 批准号:
    09460145
  • 财政年份:
    1997
  • 资助金额:
    $ 32.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)

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