2003 Fiscal Year Annual Research Report

細胞の分化とがん化における大Maf群転写因子の機能解析

Research Project

Project/Area Number	13216012
Research Institution	University of Tsukuba
Principal Investigator	高橋智筑波大学, 基礎医学系, 教授 (50271896)
Keywords	転写因子 / 大Maf群タンパク質 / 白血病 / 多発性骨髄腫 / 腎臓 / 足細胞 / 糖尿病 / インシュリン
Research Abstract	大Maf群転写因子の発がんにおける機能を明らかにする目的で、c-Mafをイムノグロブリンのプロモーターとエンハンサーを用いてB細胞特異的に発現するトランスジェニックマウスを作製し、解析した。その結果、c-Mafの発現量の高い2つの異なるラインの加齢マウスでlymphomaの発症を確認した。これらの細胞はB220、CD19陽性で、車輪状の核を有し、好酸性の胞体を伴った細胞で、形態的にもplasmacytoma(骨髄腫)であった。また、CD2プロモーターを用いてT細胞特異的にc-Mafを過剰発現するマウスを作製したところ、頻度は低いものの白血病の発症が観察された。これらのことから、c-Mafの単純な過剰発現により、B細胞およびT細胞では白血病が発症することが確認された。また、これらのトランスジェニックマウスでは、B細胞およびT細胞の分化異常が認められ、それらの異常細胞が、前がん状態を形成していることが示唆された。一方、昨年度作製したMafBおよびMafA欠損マウスの表現型の解析を行った。MafB欠損マウスでは、糸球体足細胞の足突起の形成不全があることが明らかになっていたが、MafB欠損足細胞ではスリット膜形成に不可欠なnephrinおよびpodocinの発現が有意に減少していることが明らかになった。また、データベースのサーチによりnephrinおよびpodocinの転写調節領域にMaf群タンパク質の結合配列が存在することが確認され、これら2つの遺伝子が、MafBの標的であることが示唆された。一方、MafA欠損マウスでは、インシュリンの産生量の低下、耐糖能の異常があることが明らかとなった。また、細胞レベルの実験でMafAがインシュリン遺伝子の制御領域に直接結合することを明らかにした。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Morita M, et al.: "HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin."EMBO J.. 22. 1134-1146 (2003)
[Publications] Yokoyama H, et al.: "Regulation of YB-1 gene expression by GATA transcription factors."Biochem Biophys Res Commun.. 303. 140-145 (2003)
[Publications] Morita M, et al.: "Functional analysis of basic transcription element binding protein by gene targeting technology."Mol Cell Biol.. 23. 2489-2500 (2003)
[Publications] Hirayama A, et al.: "EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice."Free Radical Biol.Med.. 34. 1236-1242 (2003)
[Publications] Hirotsune S, et al.: "An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene."Nature.. 423. 91-96 (2003)
[Publications] Moriguchi T, et al.: "Distinct response to dioxin in an arylhydrocarbon receptor (AhR)-humanized mouse."Proc Nat Acad Sci.USA. 100. 5652-5657 (2003)
[Publications] Minegishi N, et al.: "Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos."Blood.. 102. 896-905 (2003)
[Publications] Wakabayashi J, et al.: "GATA-1 testis activation region is essential for Sertoli cell-specific expression of GATA-1 gene in transgenic mouse."Gene Cells.. 7. 619-630 (2003)
[Publications] Hamada M, et al.: "The mouse maf B 5'-upstream fragment directs gene expression in myelomonocytic cells, differentiated macrophages and the ventral spinal cord in transgenic mice."J Biochem.. 134. 203-210 (2003)
[Publications] Yoh K, et al.: "Transgenic overexpression of GATA-3 in Tlymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background."J Am Soc Nephrol.. 14. 2494-2502 (2003)
[Publications] Wakabayashi N, et al.: "Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation."Nat Genet.. 35. 238-245 (2003)
[Publications] Morito N, et al.: "Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels."Oncogene.. 22. 9275-9281 (2003)
[Publications] Terunuma T, et al.: "Effect of acoustic stress on glucocorticoid receptor mRNA in the cochlea of the guinea pig."Mol Brain Res.. 120. 65-72 (2003)
[Publications] Kajihara M, et al.: "Mouse MafA, homologue of zebrafish Somite Maf1 contributes to the specific transcriptional activity through the insulin promoter."Biochem Biophys Res Commun.. 312. 831-842 (2003)
[Publications] Morito N, et al.: "Nrf2-deficiency improves autoimmune nephritis caused by the fas mutation lpr."Kidney Int.. (in press).
[Publications] Nakatani K, et al.: "Endothelial adhesion molecules in glomerular lesions : Association with their severity and diversity in lupus models."Kidney Int.. (in press).

2003 Fiscal Year Annual Research Report

細胞の分化とがん化における大Maf群転写因子の機能解析

Principal Investigator

高橋 智 筑波大学, 基礎医学系, 教授 (50271896)

Research Products

[Publications] Morita M, et al.: "HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin."EMBO J.. 22. 1134-1146 (2003)

[Publications] Yokoyama H, et al.: "Regulation of YB-1 gene expression by GATA transcription factors."Biochem Biophys Res Commun.. 303. 140-145 (2003)

[Publications] Morita M, et al.: "Functional analysis of basic transcription element binding protein by gene targeting technology."Mol Cell Biol.. 23. 2489-2500 (2003)

[Publications] Hirayama A, et al.: "EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice."Free Radical Biol.Med.. 34. 1236-1242 (2003)

[Publications] Hirotsune S, et al.: "An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene."Nature.. 423. 91-96 (2003)

[Publications] Moriguchi T, et al.: "Distinct response to dioxin in an arylhydrocarbon receptor (AhR)-humanized mouse."Proc Nat Acad Sci.USA. 100. 5652-5657 (2003)

[Publications] Minegishi N, et al.: "Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos."Blood.. 102. 896-905 (2003)

[Publications] Wakabayashi J, et al.: "GATA-1 testis activation region is essential for Sertoli cell-specific expression of GATA-1 gene in transgenic mouse."Gene Cells.. 7. 619-630 (2003)

[Publications] Hamada M, et al.: "The mouse maf B 5'-upstream fragment directs gene expression in myelomonocytic cells, differentiated macrophages and the ventral spinal cord in transgenic mice."J Biochem.. 134. 203-210 (2003)

[Publications] Yoh K, et al.: "Transgenic overexpression of GATA-3 in Tlymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background."J Am Soc Nephrol.. 14. 2494-2502 (2003)

[Publications] Wakabayashi N, et al.: "Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation."Nat Genet.. 35. 238-245 (2003)

[Publications] Morito N, et al.: "Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels."Oncogene.. 22. 9275-9281 (2003)

[Publications] Terunuma T, et al.: "Effect of acoustic stress on glucocorticoid receptor mRNA in the cochlea of the guinea pig."Mol Brain Res.. 120. 65-72 (2003)

[Publications] Kajihara M, et al.: "Mouse MafA, homologue of zebrafish Somite Maf1 contributes to the specific transcriptional activity through the insulin promoter."Biochem Biophys Res Commun.. 312. 831-842 (2003)

[Publications] Morito N, et al.: "Nrf2-deficiency improves autoimmune nephritis caused by the fas mutation lpr."Kidney Int.. (in press).

[Publications] Nakatani K, et al.: "Endothelial adhesion molecules in glomerular lesions : Association with their severity and diversity in lupus models."Kidney Int.. (in press).

高橋智筑波大学, 基礎医学系, 教授 (50271896)