2001 Fiscal Year Annual Research Report

生体分子の修飾・制御システムの異常による発がん機構

Research Project

Project/Area Number	13214086
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	Kumamoto University
Principal Investigator	中尾光善熊本大学, 発生医学研究センター, 教授 (00217663)
Keywords	エピジェネティクス / DNAメチル化 / クロマチン / メチル化CpG結合タンパク質 / 翻訳後修飾 / タンパク質分解 / ユビキチンリガーゼ / がん
Research Abstract	生体内の遺伝子やタンパク質の機能は選択的に活性化または不活性化されており、広くはエピジェネティクスの概念で捉えられる。とりわけ、DNAメチル化とクロマチンによる転写調節、細胞内タンパク質の翻訳後修飾と分解による機能分子の代謝的安定性、それらの制御異常が発がん機構として重要であることが明確になってきた。本研究を通して、[1]DNAメチル化とクロマチンについて、メチル化CpG結合タンパク質MBD1の転写抑制ドメィンはヒストン脱アセチル化酵素に依存せず、新規メディエーターMCAFを介して転写開始複合体を直接阻害することが判明した。これは他のメチル化CpG結合タンパク質がヒストン脱アセチル化酵素と共役することと対比される。癌細胞でメチル化されたp16遺伝子の転写抑制に関与しており、発がん関連性が示唆された。また、NMR構造解析によって、メチル化CpGとMBD1のメチル化DNA結合ドメインの複合体構造を解明した。[2]細胞内タンパク質の翻訳後修飾と分解について、新しいHect型ユビキチンリガーゼhHYDがDNA損傷・修復に関わる新しいユビキチン化経路で働いており、トポイソメラーゼ関連タンパク質TopBP1が基質のひとつであった。また、血清による細胞増殖と分化を司る転写因子SRFがPML核内ボディでヒストンアセチル化酵素と相互作用してc-fos遺伝子などを転写活性化すること、SRFのDNA結合ドメイン内のSUMO-1化で負に調節されることを明らかにした。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Ohki, I.: "Solution structure of the methyl-CpG-binding domain of human MBD1 in complex with a methylated DNA"Cell. 105. 487-497 (2001)
[Publications] Takizawa, T.: "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain"Dev. Cell. 1. 749-758 (2001)
[Publications] Meguro, M.: "A novel maternally expressed gene, ATP1OC, encodes a putative aminophospholipid translocase associated with Angelman syndrome"Nature Genet.. 28. 19-20 (2001)
[Publications] Nakao, M.: "Epigenetics : interactions of DNA methylation and chromatin"Gene. 278. 25-31 (2001)
[Publications] Honda, Y.: "Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response"J. Biol. Chem.. (in press).
[Publications] EL-Gazzar, M.A.: "PU.1 is involved in the regulation of B lineage-associated and developmental stage-dependent expression of the germinal center-associated DNA-primase GANP"J. Biol. Chem.. 276. 48000-48008 (2001)
[Publications] Kino, T.: "Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma"Genes Cells. 6. 441-454 (2001)
[Publications] Takebayashi, S.: "5-aza-2'-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation"Biochem. Biophys. Res. Commun.. 288. 921-926 (2001)
[Publications] Meguro, M.: "Large-scale evaluation of imprinting status in the Prader-Willi syndrome region : an imprinted direct repeat cluster resembling small nucleolar RNA genes"Hum. Mol. Genet.. 10. 83-394 (2001)
[Publications] Sudo, T.: "Activation of Cdh1-dependent APC is required for G1 cell cycle arrest and DNA damage-induced G2 checkpoint in vertebrate cells"EMBOJ.. 20. 6499-6508 (2001)
[Publications] Kaneko, T.: "Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas"Cancer. 92. 2662-2672 (2001)
[Publications] Nakao, M.: "Regulation of transcription and chromatin by methyl-CpG binding protein MBD1"Brain Dev.. 23 Suppl1. S174-S176 (2001)

2001 Fiscal Year Annual Research Report

生体分子の修飾・制御システムの異常による発がん機構

Principal Investigator

中尾 光善 熊本大学, 発生医学研究センター, 教授 (00217663)

Research Products

[Publications] Ohki, I.: "Solution structure of the methyl-CpG-binding domain of human MBD1 in complex with a methylated DNA"Cell. 105. 487-497 (2001)

[Publications] Takizawa, T.: "DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain"Dev. Cell. 1. 749-758 (2001)

[Publications] Meguro, M.: "A novel maternally expressed gene, ATP1OC, encodes a putative aminophospholipid translocase associated with Angelman syndrome"Nature Genet.. 28. 19-20 (2001)

[Publications] Nakao, M.: "Epigenetics : interactions of DNA methylation and chromatin"Gene. 278. 25-31 (2001)

[Publications] Honda, Y.: "Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response"J. Biol. Chem.. (in press).

[Publications] EL-Gazzar, M.A.: "PU.1 is involved in the regulation of B lineage-associated and developmental stage-dependent expression of the germinal center-associated DNA-primase GANP"J. Biol. Chem.. 276. 48000-48008 (2001)

[Publications] Kino, T.: "Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma"Genes Cells. 6. 441-454 (2001)

[Publications] Takebayashi, S.: "5-aza-2'-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation"Biochem. Biophys. Res. Commun.. 288. 921-926 (2001)

[Publications] Meguro, M.: "Large-scale evaluation of imprinting status in the Prader-Willi syndrome region : an imprinted direct repeat cluster resembling small nucleolar RNA genes"Hum. Mol. Genet.. 10. 83-394 (2001)

[Publications] Sudo, T.: "Activation of Cdh1-dependent APC is required for G1 cell cycle arrest and DNA damage-induced G2 checkpoint in vertebrate cells"EMBOJ.. 20. 6499-6508 (2001)

[Publications] Kaneko, T.: "Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas"Cancer. 92. 2662-2672 (2001)

[Publications] Nakao, M.: "Regulation of transcription and chromatin by methyl-CpG binding protein MBD1"Brain Dev.. 23 Suppl1. S174-S176 (2001)

中尾光善熊本大学, 発生医学研究センター, 教授 (00217663)