MOLECULAR MECHANISMS OF ACCELERATED ERYTHROID APOPTOSIS DUE TO A GLYCOLYTIC ENZYME DEFECT

糖酵解酶缺陷加速红细胞凋亡的分子机制

基本信息

  • 批准号:
    14570131
  • 负责人:
  • 金额:
    $ 2.18万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2002
  • 资助国家:
    日本
  • 起止时间:
    2002 至 2003
  • 项目状态:
    已结题

项目摘要

Pyruvate kinase (PK) deficiency is one of the most prevalent causes of hereditary non-spherocytic hemolytic anemia due to glycolytic enzyme defects. We previously reported that hemolytic anemia of the Pk-1^<slc> mouse was due to a spontaneous mutant of the murine PKLR gene. Apoptotic erythroid cells were notably increased in spleen, and the transgenic rescue of the Pk-1^<slc> decreased apoptotic erythroid cells in the mutant spleen. SLC3 is a Friend erythroleukemic cell, which has been established from the Pk-1^<slc> mouse. The cell shows spontaneous apoptosis during routine passage and is more susceptible to apoptosis compared to control Friend cells, which is inducible with either glucose deprivation or glucose analogue, 2-deoxyglucose.In this study, possible adverse effects of PK deficiency on the maturation of erythroid progenitors were investigated. A four-year-old Japanese girl with severe PK deficiency underwent splenectomy to reduce her need for blood transfusions. The spleen w … More as examined a histologically and the hematopoietic progenitors in the spleen were assayed to evaluate the extramedullary hematopoiesis of the PK-deficient subject. The number of hematopoietic progenitors including CFU-GM, BFU-E and CFU-GEMM in the spleen of the PK-deficient patient was much higher than those found in control spleens, indicating enhanced extramedullary hematopoiesis. The TUNEL assay demonstrated apoptotic cells in the splenic red pulp of the PK-deficient patient. The expression of 7A6 antigen was detected in cells isolated from spleen and in cells cultured in vitro, but only in those cells that were positive for glycophorin A. These results provide evidence that the metabolic disturbances in PK deficiency affect not only the survival of red cells but also the maturation of erythroid progenitors, which results in premature cell death, i.e., apoptosis.To evaluate an involvement of R-PK in apoptosis of SLC3, we established two stable-transfectants with wild-type human R-PK cDNA, SLC3-hRPK.hi and lo, and examined gene expression profiles of these cells. DNA microarray analysis were performed by using Affymetrix GeneChip Mouse Expression Array 430A, and totally 22690 genes were analyzed. Approximately 7% of genes were significantly down-regulated both in SLC3-hRPK.hi and lo, including genes for ε-globin, erythropoietin receptor, β-spectrin, glycophorin A, or Rh-associated A glycoprotein. On the other hand, up-regulated genes was only about 0.2%, such as subtypes H1c and H2bc of histone 1, kcne3 potassium voltage-gated channel or adult α-globin.We identified that gene expression of several pro-apoptotic genes such as Bnip31, Pdcd6ip, Casp8ap2, Faf1 and Blk was significantly down-regulated by introducing RPK. These observations suggest that forced expression of RPK facilitated globin gene switching and terminal erythroid differentiation. Further studies will require elucidating mechanisms for apoptosis due to RPK deficiency. Less
丙酮酸激酶(PK)缺乏是遗传性非球形红细胞溶血性贫血的最常见原因之一,由于糖酵解酶缺陷。我们以前报道过Pk-1^小鼠的溶血性贫血<slc>是由于鼠PKLR基因的自发突变。凋亡的红系细胞在脾脏中显著增加,并且Pk-1 α的转基因拯救<slc>减少了突变体脾脏中的凋亡的红系细胞。SLC 3是一种Friend红白血病细胞,已从Pk-1^小鼠中建立<slc>。该细胞在常规传代过程中表现出自发性凋亡,并且与对照Friend细胞相比更容易发生凋亡,而对照Friend细胞可以用葡萄糖剥夺或葡萄糖类似物2-deoxyglucose.In这项研究中,PK缺乏对红系祖细胞成熟可能产生的不利影响进行了研究。一名患有严重PK缺乏症的4岁日本女孩接受了脾切除术,以减少输血需求。脾W ...更多信息 如组织学检查,并测定脾中的造血祖细胞以评价PK缺陷受试者的髓外造血。PK缺陷患者脾脏中的造血祖细胞包括CFU-GM、BFU-E和CFU-GEMM的数量远高于对照脾脏中发现的那些,表明髓外造血增强。TUNEL法显示PK缺陷患者的脾红髓中存在凋亡细胞。7A 6抗原在脾细胞和体外培养的细胞中均有表达,但仅在血型糖蛋白A阳性的细胞中有表达。这些结果提供了PK缺乏中的代谢紊乱不仅影响红细胞的存活而且影响红系祖细胞的成熟的证据,这导致过早的细胞死亡,即,为了评估R-PK在SLC 3细胞凋亡中的参与,我们建立了两个具有野生型人R-PK cDNA的稳定转染子,SLC 3-hRPK.hi和lo,并检测了这些细胞的基因表达谱。使用Affyscore GeneChip Mouse Expression Array 430 A进行DNA微阵列分析,共分析了22690个基因。约7%的基因在SLC 3-hRPK.hi和lo中均显著下调,包括ε-珠蛋白、促红细胞生成素受体、β-血影蛋白、血型糖蛋白A或Rh相关A糖蛋白的基因。另一方面,上调的基因仅约0.2%,如组蛋白1的H1 c和H2 bc亚型、kcne 3钾电压门控通道或成人α-珠蛋白。我们发现,通过引入RPK,Bnip 31、Pdcd 6 ip、Casp 8ap 2、Faf 1和Blk等几个促凋亡基因的基因表达明显下调。这些观察结果表明,RPK的强制表达促进珠蛋白基因转换和终末红细胞分化。进一步的研究将需要阐明由于RPK缺陷引起的细胞凋亡的机制。少

项目成果

期刊论文数量(25)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Morimoto A, Ueda I, Hirashima Y, Sawai Y, Usuku T, Kano G, Kuriyama K, Todo S, Sugimoto T, Kanno H, Fujii H, Imashuku S: "A novel missense mutation (1060G→C) in the phosphoglycerate kinase gene in a Japanese boy with chronic hemolytic anemia, developmenta
Morimoto A、Ueda I、Hirashima Y、Sawai Y、Usuku T、Kano G、Kuriyama K、Todo S、Sugimoto T、Kanno H、Fujii H、Imashuku S:“磷酸甘油酸激酶中的一种新型错义突变 (1060G→C)患有慢性溶血性贫血的日本男孩的基因,正在发育
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  • 影响因子:
    0
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Murakami K, Kanno H, Tancabelic J, Fujii H: "Gene expression and biological significance of hexokinase in erythroid cells."Acta Haematol. 108. 204-209 (2002)
Murakami K、Kanno H、Tancabelic J、Fujii H:“红系细胞中己糖激酶的基因表达和生物学意义。”Acta Haematol。
  • DOI:
  • 发表时间:
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  • 影响因子:
    0
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Sakimoto, T. et al.: "A novel nonsense mutation with a compound heterozygous mutation in TGFBI gene in lattice corneal dystrophy type I"Jpn J Ophthalmol. 47. 13-17 (2003)
Sakimoto, T. 等人:“I 型格子角膜营养不良中 TGFBI 基因中具有复合杂合突变的新型无义突变”Jpn J Ophamol。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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  • 通讯作者:
Kanno H et al.: "Phrsiological significance and molecular genetics of red cell enzymes involved in the ribonucleotide metabolism"Proc Jpn Acad. 78. 287-292 (2002)
Kanno H 等人:“参与核糖核苷酸代谢的红细胞酶的生理学意义和分子遗传学”Proc Jpn Acad。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Kanno, H. et al.: "Homozygous intragenic deletion of type-I hexokinase gene causes lethal hemolytic anemia of the affected fetus"BLOOD. 100. 1930 (2002)
Kanno, H. 等人:“I 型己糖​​激酶基因的纯合基因内缺失会导致受影响胎儿发生致命的溶血性​​贫血”BLOOD。
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    0
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KANNO Hitoshi其他文献

Traditional Craftwork and Rural Community : A case study on the Choma textile production in Japan.
传统手工艺和农村社区:日本 Choma 纺织品生产的案例研究。
集団就職世代のライフヒストリ--成功者たちの回想を中心にして
集体就业一代的人生史--聚焦成功人士的回忆
  • DOI:
  • 发表时间:
    2005
  • 期刊:
  • 影响因子:
    0
  • 作者:
    KATO Masayoshi;KANNO Hitoshi;黒田 英一
  • 通讯作者:
    黒田 英一
Ex-Vivo Expanded NK Cell Therapy Combined with Elotuzumab for MRD after Autologous Stem Cell Transplantation: A Phase I/ II Clinical Trial in Progress.
体外扩展 NK 细胞疗法联合 Elotuzumab 用于自体干细胞移植后 MRD:正在进行的 I/II 期临床试验。
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    HAGIWARA Shotaro;WANG Yan-Hua;KOBAYASHI Hirohito;KATO Yutaka;TANAKA Norina;IIZUKA Yuki;WATANABE Aya;ISHIYAMA Midori;SHINOHARA Akihito;KAZAMA Hiroshi;YOSHINAGA Kentaro;SHISEKI Masayuki;KANNO Hitoshi;TANAKA Junji
  • 通讯作者:
    TANAKA Junji

KANNO Hitoshi的其他文献

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{{ truncateString('KANNO Hitoshi', 18)}}的其他基金

Andic properties and those spatial variability of Fulvic Andosols-related soils in certain hilly areas of northeastern Japan
日本东北部某些丘陵地区与黄腐安土相关的土壤的安第斯特性和空间变异
  • 批准号:
    23580085
  • 财政年份:
    2011
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Development of novel gene therapy for congenital blood disorders using induced pluripotent stem cells
利用诱导多能干细胞开发治疗先天性血液疾病的新型基因疗法
  • 批准号:
    22591071
  • 财政年份:
    2010
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Physiological significance of pyruvate kinase isozymes in erythrocyte.
红细胞中丙酮酸激酶同工酶的生理意义。
  • 批准号:
    11670153
  • 财政年份:
    1999
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Regulation of human pyruvate kinase gene in red cells
红细胞中人丙酮酸激酶基因的调控
  • 批准号:
    09670165
  • 财政年份:
    1997
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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MFB:移码刺激器的RNA修饰:通过计算突变预测和功能实验来设计基因表达的细胞平台
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Developing a new generation of tools for predicting novel AMR mutation profiles using generative AI
使用生成人工智能开发新一代工具来预测新型 AMR 突变谱
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    2024
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The mechanism of oral carcinogenesis by FAT1 gene mutation
FAT1基因突变导致口腔癌的机制
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通过同时诱导串联重复扩增和突变来创建多基因家族的挑战
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    23K14172
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一种用于综合体细胞嵌合突变检测的无参考计算算法
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    10662755
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    2023
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Somatic mutation rates in healthy aging
健康老龄化中的体细胞突变率
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具有 H3K27M 突变的弥漫性中线胶质瘤的表观遗传依赖性
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