Regulation of erythroid differentiation by trnscription factors and heme
转录因子和血红素对红细胞分化的调节
基本信息
- 批准号:08458188
- 负责人:
- 金额:$ 5.31万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:1996
- 资助国家:日本
- 起止时间:1996 至 1997
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
1) We showed that dimethyl sulfoxide increased the eryThroid transcription factor NF-E2' DNA complex formation in the wild -type MEL cells, in part by the induction of p45 gene expression, and that both DNA binding and transactivation activity of NF-E2 are regulated by Ser/Thr phosphorylation suchas Ras siganling cascade. An Mafk homodimer may suppress transcription not only by competition for the DNA binding site, but also by directly inhibiting transcription.2) Using a yeast two-hybrid screen with a GAL4-MafK fusion protein, we identified two novel bZip transcription factors, Bach1 and Bach2, as heterodimerization partners of MafK, In addition to a CNC-type bZip domain, these Bach proteins possess another protein interaction motif, BTB domain. Expression of Bach1 appears ubiquitous, but that of Bach2 is restricted to monocytes and neuronal cells. Bach proteins bind in vitro to NF-E2 binding sites by forming heterodimers with MafK.Bach1 and Bach2 function as transcription repressors i … More n transfection assays using fibroblast cells, but they function as a transcription activator and repressor, respectively, in cultured erythroid cells.3) A short amino acid sequence, the heme regulatory motif (HRM), has been shown to be involved in the hemin inhibition of protein transport into mitochondria in vitro. To elucidate the role of HRM in the home regulation of 5-aminolevulinate synthase (ALAS) transport in vivo, we constructed a series of mutants of the non-specific isoform of ALAS (ALAS-N) in which the specific cysteine residues within the HRMs were converted to serines. Wild-type and mutant enzymes were expressed in QT6 fibroblasts through transient transfection, followed by analyses of the mitochondrial import of the enzymes. The home inhibition, which was observed in the wild-type ALAS-N, abolished completely when all the three HRMs in the enzyme were mutated, indicating that the FIRM is actually required for the heme regulation of ALAS-N transport within the cells. In contrast, exogenous hemin did not affect the import of the erythroid ALAS (ALAS-E) under the comparable experimental conditions.4) We analyzed ALAS-E gene (ALAS2) of Japanese males with pyridoxine-refractory X-l inked sideroblastic anemia (XLSA) and identified an ALAS2 mutation (D19OV). The mutation did not affect the enzyme activity in vitro. However, the amount of the enzyme in bone marrow cells were found to be reduced to approximately 5% of the normal control. Additionally, accumulation of aberrantly processed proteins, the sizes of which were larger than that of mature ALAS-E, was found in mitochondria in transient transfection analyses. These larger products were reproducibly detected in assays combining in vitro transcription/translation and precursor import into isolated mitochondria. These results indicate that the mutation causing pyridoxine-refractory XLSA may affect the processing of ALAS-E precursor, thus provoking instability of the ALAS-E protein. Less
1)我们发现,二甲基亚砜增加了野生型MEL细胞中红细胞类转录因子NF-E2 ' DNA复合物的形成,部分是通过诱导p45基因表达,并且NF-E2的DNA结合和反式激活活性都受到Ser/Thr磷酸化如Ras信号级联的调节。Mafk同源二聚体不仅可以通过竞争DNA结合位点抑制转录,还可以直接抑制转录。2)利用GAL 4-MafK融合蛋白的酵母双杂交筛选,我们鉴定了两个新的bZip转录因子Bach 1和Bach 2,它们是MafK的异源二聚体伴侣。Bach 1的表达似乎是普遍存在的,但Bach 2的表达仅限于单核细胞和神经元细胞。Bach蛋白在体外通过与MafK形成异二聚体与NF-E2结合位点结合,Bach 1和Bach 2作为转录抑制因子发挥作用。 ...更多信息 在使用成纤维细胞的转染试验中,它们的功能是转录激活子和阻遏子,但在培养的红细胞中,它们分别起转录激活子和阻遏子的作用。3)一个短的氨基酸序列,血红素调节基序(HRM),已被证明参与氯化血红素在体外抑制蛋白质转运到线粒体中。为了阐明HRM在体内5-氨基乙酰丙酸合酶(ALAS)转运的家庭调节中的作用,我们构建了一系列ALAS的非特异性同种型(ALAS-N)的突变体,其中HRM内的特异性半胱氨酸残基被转化为丝氨酸。野生型和突变型酶通过瞬时转染在QT 6成纤维细胞中表达,随后分析酶的线粒体输入。当酶中的所有三个HRM突变时,在野生型ALAS-N中观察到的家庭抑制完全消除,表明FIRM实际上是细胞内ALAS-N运输的血红素调节所需的。相反,在可比的实验条件下,外源性氯化血红素不影响红系ALAS(ALAS-E)的输入。4)我们分析了患有吡哆醇难治性X-1连锁铁粒幼细胞性贫血(XLSA)的日本男性的ALAS-E基因(ALAS 2),并鉴定了ALAS 2突变(D19 OV)。该突变对体外酶活无影响。然而,发现骨髓细胞中的酶的量减少到正常对照的约5%。此外,在瞬时转染分析中,在线粒体中发现异常加工的蛋白质的积累,其尺寸大于成熟ALAS-E的尺寸。这些较大的产物在结合体外转录/翻译和前体导入分离的线粒体的测定中可重复地检测到。这些结果表明,导致吡哆醇难治性XLSA的突变可能影响ALAS-E前体的加工,从而引起ALAS-E蛋白的不稳定性。少
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nagai, M., Nagai, T., Yamamoto, M., Goto, K., Bishop, T.R., Hayashi, N., Kondo, H., Seyama, Y., Kano, K., Fujita, H., Sassa, S.: "Novel regulation of d-aminolevulinate synthase in the rat Harderian gland." Biochem.Pharmacol.53. 643-650 (1997)
Nagai, M.、Nagai, T.、Yamamoto, M.、Goto, K.、Bishop, T.R.、Hayashi, N.、Kondo, H.、Seyama, Y.、Kano, K.、Fujita, H.、Sassa
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Minegishi, Naoko: "Expression of GATA transcription factors in myelogenous and lymphoblastic leukemia cells" Int. J. Hematol.印刷中. (1997)
Minegishi, Naoko:“GATA 转录因子在骨髓和淋巴细胞白血病细胞中的表达”,Int. J. Hematol,出版中。
- DOI:
- 发表时间:
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- 影响因子:0
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- 通讯作者:
Oyake,Tatsuya: "Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site." Mol.Cell.Biol.16. 6083-6095 (1996)
Oyake, Tatsuya:“Bach 蛋白属于 BTB 碱性亮氨酸拉链转录因子的一个新家族,它与 MafK 相互作用并通过 NF-E2 位点调节转录。”
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- 发表时间:
- 期刊:
- 影响因子:0
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Furuyama, K., Fujita, H., Nagai, T., Yomogida, K., Munakata, H., Kondo, M., Kimura, A., Kuramoto, A., Hayashi, N., Yamamoto, M.: "Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase ge
Furuyama, K.、Fujita, H.、Nagai, T.、Yomogida, K.、Munakata, H.、Kondo, M.、Kimura, A.、Kuramoto, A.、Hayashi, N.、Yamamoto, M.:
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Nagai, T., Harigae, H., Furuyama, K., Munakata, H., Hayashi, N., Endo, K., Sassa, S., Yamamoto, M.: "5-aminolevulinate synthase expression and hemoglobin synthesis in a human myelogenous leukemia cell line." J.Biochem.(Tokyo). 121. 487-495 (1997)
Nagai, T.、Harigae, H.、Furuyama, K.、Munakata, H.、Hayashi, N.、Endo, K.、Sassa, S.、Yamamoto, M.:“5-氨基乙酰丙酸合酶表达和血红蛋白合成
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HAYASHI Norio其他文献
HAYASHI Norio的其他文献
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{{ truncateString('HAYASHI Norio', 18)}}的其他基金
System identification of physiological-psychological horticultural activity effect system using hands palm
手掌生理心理园艺活动效果系统识别
- 批准号:
20688011 - 财政年份:2008
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Young Scientists (A)
Epithelial transformation by stroma transplant in urogenital organs
泌尿生殖器官基质移植的上皮转化
- 批准号:
16591631 - 财政年份:2004
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Regulation of dendritic cell function and cell-based therapy in chronic hepatitis C virus infection
慢性丙型肝炎病毒感染中树突状细胞功能的调节和细胞治疗
- 批准号:
15109006 - 财政年份:2003
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$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (S)
PROMOTING EFFECTS OF JUVENILE ESTROGEN TREATMENT ON DEVELOPMENT OF AUTOIMMUNE PROSTATITIS IN NEONATALLY THYMECTOMIZED MICE
幼年雌激素治疗对新生胸腺切除小鼠自身免疫性前列腺炎发展的促进作用
- 批准号:
13671684 - 财政年份:2001
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Therapeutic strategy for hepatocellular carcinoma by dendritic cell-based tumor vaccination
基于树突状细胞的肿瘤疫苗接种治疗肝细胞癌的策略
- 批准号:
12557054 - 财政年份:2000
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Therapetic strategy for chronic hepatitis C by inducing apoptosis of hepatocyte infected with hepatitis C virus
诱导丙型肝炎病毒感染肝细胞凋亡治疗慢性丙型肝炎的治疗策略
- 批准号:
11470132 - 财政年份:1999
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B).
Roles of heme in the regulation of gene expression and cell differentiation of erythroid cells
血红素在红系细胞基因表达和细胞分化调节中的作用
- 批准号:
10480163 - 财政年份:1998
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Cytodifferentiation on cancer of urogenital tract organs via cell to cell interaction
通过细胞间相互作用进行泌尿生殖道器官癌症的细胞分化
- 批准号:
10671468 - 财政年份:1998
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Gene manipulation of heme synthetic pathway enzymes
血红素合成途径酶的基因操作
- 批准号:
10557015 - 财政年份:1998
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Therapeutic approach to hepatitis C by regulation of apoptosis-related gene
调控凋亡相关基因治疗丙型肝炎
- 批准号:
08457167 - 财政年份:1996
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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