1996 Fiscal Year Annual Research Report

赤血球特異的な遺伝子発現の分子機構

Research Project

Project/Area Number	08265204
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
Research Institution	University of Tsukuba
Principal Investigator	山本雅之筑波大学, 基礎医学系, 教授 (50166823)
Co-Investigator(Kenkyū-buntansha)	峯岸直子東北大学, 医学部, 助手 (40271895)
Keywords	転写因子 / 赤血球 / 細胞分化 / GATA-1 / GATA-2 / NF-E2 / CNCファミリー / 造血幹細胞
Research Abstract	赤血球特異的な遺伝子発現制御機構を解明する目的で,転写因子間相互作用に基づく転写制御ネットワークが赤血球前駆細胞の増殖・分化の方向性決定に果たす役割の解明と,赤血球系転写因子自身の発現制御機構の解明とを試みた.その結果,以下の点を明らかにした. 1.GATA-1の転写制御機構が胎児型造血細胞と成人型造血細胞とで異なることを発見した.また,GATA-1遺伝子の部分破壊により,同遺伝子が胎児型造血細胞・成人型造血細胞それぞれの成熟過程に必須であることを実証した. 2.NF-E2転写因子の小サブユニットであるMafKの転写が造血細胞・間葉細胞と神経細胞との間で異なるプロモーターにより,独立に制御されることを発見した. 3.NF-E2の大サブユニットであるCNCファミリー蛋白質と会合し,その細胞内局在を制御する新しい蛋白質Keap1を発見し,その構造と機能を解析した. 4.GATA-2遺伝子の転写制御には2つの異なるプロモーターが関与しており,造血細胞で特異的に機能するプロモーターが存在することを明らかにした. 本研究において,GATA-1遺伝子部分破壊マウスの解析から,GATA-1が胎児造血細胞分化に必須であることが理解された.ところで,個体レベルで遺伝子破壊を行い,その表現型の変化を調べる方法の問題点は,その個体が胎生致死となった際に,原因となった細胞系列以外に対する影響を解析できない点にある.GATA-1遺伝子破壊マウスでは,成人造血細胞に対するGATA-1欠失効果を解析できない.そこで,試験管内で胚幹細胞を血球分化させる系や,ネオマイシン耐性遺伝子をLoxP配列に挟んだ形で挿入した部分破壊マウス系の確立に取り組んでいる.今後は,これらシステムを用いて,造血細胞の増殖・分化に対するGATA-1の機能的貢献や,さらに胎児造血と成人造血の関係等を検討する予定である.

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Jippo,T.: "Abundant expression of GATA-2 in proliferating but not in differentaited mast cells in tissues of mice ; demonstration by in situ bybridization" Blood. 87巻. 993-998 (1996)
[Publications] Motohashi,H.: "Mesodermal-versus neuronal-specific expression of Mafk is elicited by different promoters" Genes Cells. 1巻. 223-238 (1996)
[Publications] Komatsu,N.: "Establishment and characterization of the thrombopoietin-dependent magatarycytic cell line,VT-7/TPO." Blood. 87巻. 4552-4560 (1996)
[Publications] Toki,T.: "Abundant expression of erythroid transcription factor p45 NF-E2 mRNA in human peripheral granulocytes." Biochem Biophys.Res Commun.219巻. 760-765 (1996)
[Publications] Oyake,T.: "A novel family of BTB-bZip transcription factors BACH that interact with Mafk and regulatetranscription through NF-E2 site." Mol.Cell.Biol.16巻. 6083-6095 (1996)
[Publications] Kato,S.: "Differentiation-dependent enhanced expression of protein phosphatase 2C in germ cells of mouse seminiferous tubules." FEBS Lett.396巻. 293-297 (1996)
[Publications] Ohtsu,H.: "Histidine decarboxylase expression in mouse mast cell line p815 is induced by mouse peritoneal carity incubation" J.Biol.Chem.271巻. 28439-28444 (1996)
[Publications] Minegishi,N.: "Expression of GATA transcription factors in myelogehous and lymphoblastic leakemia cells." Int,J.Hematol. (印刷中).
[Publications] Nagai,M.: "Novel regulation of δ-aminolevulinate synthase rat Harderian gland," Biochem.Pharmacol,. (印刷中).
[Publications] Onodera,K.: "Conserved stracture,regulatory elements and transcriptional regulation from the GATA-1 gene testis promoter" J,Biochem.121巻. 251-263 (1997)
[Publications] Toki,T.: "Human small Maf proteins form heterodimers with CNC family transcription factors and recognize NF-E2 motif" Oncogene. (印刷中).
[Publications] Nagai,T.: "5-Aminolevulinate synthase expression and hemoglobin synthesis in a human myelogenous leakemia cell line" J.Biochem.121巻. 487-495 (1997)
[Publications] Imagawa,S.: "Negative regalation of the erythropoietin gene expression by the GATA transcription factors." Blood. (印刷中).
[Publications] Yamamoto,M.: "Upstream and downstream of erythroid transcription factor GATA-1" Genes to Cells. (印刷中).
[Publications] Takahashi,S.: "Arrest in erythroid cell development by promoter-specitic tisruption of GATA-1 gene" J.Biol,Chem.(印刷中).
[Publications] Onodera,K.: "GATA-1 transcription in controlled by distinctiregulatory mechanisms during primitive and definitive erythropoiesis" Proc.Natl,Acad,Sci,USA. (印刷中).

1996 Fiscal Year Annual Research Report

赤血球特異的な遺伝子発現の分子機構

Principal Investigator

山本 雅之 筑波大学, 基礎医学系, 教授 (50166823)

Research Products

[Publications] Jippo,T.: "Abundant expression of GATA-2 in proliferating but not in differentaited mast cells in tissues of mice ; demonstration by in situ bybridization" Blood. 87巻. 993-998 (1996)

[Publications] Motohashi,H.: "Mesodermal-versus neuronal-specific expression of Mafk is elicited by different promoters" Genes Cells. 1巻. 223-238 (1996)

[Publications] Komatsu,N.: "Establishment and characterization of the thrombopoietin-dependent magatarycytic cell line,VT-7/TPO." Blood. 87巻. 4552-4560 (1996)

[Publications] Toki,T.: "Abundant expression of erythroid transcription factor p45 NF-E2 mRNA in human peripheral granulocytes." Biochem Biophys.Res Commun.219巻. 760-765 (1996)

[Publications] Oyake,T.: "A novel family of BTB-bZip transcription factors BACH that interact with Mafk and regulatetranscription through NF-E2 site." Mol.Cell.Biol.16巻. 6083-6095 (1996)

[Publications] Kato,S.: "Differentiation-dependent enhanced expression of protein phosphatase 2C in germ cells of mouse seminiferous tubules." FEBS Lett.396巻. 293-297 (1996)

[Publications] Ohtsu,H.: "Histidine decarboxylase expression in mouse mast cell line p815 is induced by mouse peritoneal carity incubation" J.Biol.Chem.271巻. 28439-28444 (1996)

[Publications] Minegishi,N.: "Expression of GATA transcription factors in myelogehous and lymphoblastic leakemia cells." Int,J.Hematol. (印刷中).

[Publications] Nagai,M.: "Novel regulation of δ-aminolevulinate synthase rat Harderian gland," Biochem.Pharmacol,. (印刷中).

[Publications] Onodera,K.: "Conserved stracture,regulatory elements and transcriptional regulation from the GATA-1 gene testis promoter" J,Biochem.121巻. 251-263 (1997)

[Publications] Toki,T.: "Human small Maf proteins form heterodimers with CNC family transcription factors and recognize NF-E2 motif" Oncogene. (印刷中).

[Publications] Nagai,T.: "5-Aminolevulinate synthase expression and hemoglobin synthesis in a human myelogenous leakemia cell line" J.Biochem.121巻. 487-495 (1997)

[Publications] Imagawa,S.: "Negative regalation of the erythropoietin gene expression by the GATA transcription factors." Blood. (印刷中).

[Publications] Yamamoto,M.: "Upstream and downstream of erythroid transcription factor GATA-1" Genes to Cells. (印刷中).

[Publications] Takahashi,S.: "Arrest in erythroid cell development by promoter-specitic tisruption of GATA-1 gene" J.Biol,Chem.(印刷中).

[Publications] Onodera,K.: "GATA-1 transcription in controlled by distinctiregulatory mechanisms during primitive and definitive erythropoiesis" Proc.Natl,Acad,Sci,USA. (印刷中).

山本雅之筑波大学, 基礎医学系, 教授 (50166823)