1998 Fiscal Year Annual Research Report

転写因子PEBP2の構造異常による白血病発症の機序

Research Project

Project/Area Number	09253220
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (A)
Research Institution	Kyoto University
Principal Investigator	伊藤嘉明京都大学, ウイルス研究所, 教授 (80004612)
Co-Investigator(Kenkyū-buntansha)	菅野智彦京都大学, ウイルス研究所, 助手 (10273525)
Keywords	PEBP2 / 転写因子 / AML1 / CBF / 白血病 / 発がん機構 / キメラ遺伝子 / 転写制御機構
Research Abstract	転写活性化ドメイン中のTE2サブドメインにタンパク質/タンパク質相互作用の機能ドメインの一つ、PYモチーフが存在し、それを認識するWWドメインをもったYAPを同定した。YAPは強い転写活性化能をもち、新しいタイプのコアクチベーターであることを示した。PEBP2αAのヒトcDNAの単離、その遺伝子座(6p12.3-p21.1)の決定を介し、この遺伝子が鎖骨頭蓋骨異形成症の原因遺伝子であることを示唆した。αB/AML1は核マトリックス結合タンパク質であるが、291番目のアミノ酸よりC末端側において核マトリックスに結合することを示した。AML1/MTG8にはAMLの核マトリックス結合部位はないが、AML1と同じコンバートメントに結合し、AML1と競合することが明かとなった。これがAML1/MTG8による発がん機構の重要な一側面である可能性がある。またβ/SMMHCをコードする遺伝子、β/MYH11が骨髄球特異的プロモーターの支配下にあるトランスジエニックマウスは骨髄において未分化好中球が増加しており、それはin vitroでの分化が抑制されていた。このマウスで活性型NRASを発現させると更に悪性度が増加した。これらのデータより、β/MYH11は前白血病状態を惹起することが明かになった。点突然変異が白血病発症に重要な意味を持つ可能性を示唆した。この研究成果とキメラ遺伝子がターゲット遺伝子の発現を一般に強く抑制することよりAML1のloss of functionが白血病原性を示すのではないかとの作業仮説を我々はたてている。32Dc13細胞にAML1/MTG8及びBcl-2を安定に発現させることにより、Bcl-2はAML1/MTG8の主たるターゲットではないとの結論を得た。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Yagi,R.: "A WW domain-containing Yes-associated protein(YAP)is a novel transcriptional co-activator." EMBO J.(in press).
[Publications] Kohzaki,H.: "Block of granulocytic differentiation of 32Dc13 cells by AML1/ETO(MTG8)but not by highly expressed Bcl-2." Oncogne. (in press).
[Publications] Li,J.: "Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression on osteoblastic osteosarcoma ROSI7/2.8 cells." J.Biological Chem.273. 31009-31015 (1998)
[Publications] Okada,H.: "AML1(-/-embryos so not express certain hematopoiesis-related gene transcripts including those of the PUI gene." Oncogene. 17. 2287-2293 (1998)
[Publications] Kogan,S.: "The PEBP2βMYH11 fusion created by Inv(16)(p13;q22)in myeloid leukemia impairs neutrophil maturation and contributes to granulocvtic dysplasia." Proc.Natl.Acad.Sci.USA. 95. 11863-11868 (1998)
[Publications] Kim,W.-Y.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains." EMBOJ.18. 1609-1620 (1999)
[Publications] Osato,M.: "Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias." Blood. (in press).
[Publications] Tanaka,Y.: "The chimeric protein,PEBP2β/CBFβ-S,SMMHC,disorganizes cytoplasmic stress fibers and inhibits transcriptional activation." Oncogene. 17. 699-708 (1998)
[Publications] Kanno T.: "Cytoplasmic sequestration of the polyomavirus enhapcer binding protein 2(PEBP2)/core binding factor a(CBFa)subunit by the leukemia-related PEBP2/CBFβーSMMHC fusion protein inhibits PEBP2/CBF-Mediated transactivation." Mol.Cell.Biol.18. 4252-4261 (1998)
[Publications] Chen,L.-F.: "The capacity of PEBP2αB(AML1/Cbfa2)to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix." Mol.Cell.Biol.18. 4165-4176 (1998)
[Publications] Tsuji,K.: "Expression of the PEBP2αA/AML3/CBFA1 genes is Regulated by BMP4/7 heterodimer and its overexpression suppresses type I collagen and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells." Bone. 22. 87-92 (1998)
[Publications] Ji,C.: "CBFa(AML/PEBP2)-related elements in the TGF-b type I receptor promoter and expression with osteoblast differentiation." J.Cell.Biochem.69. 353-363 (1998)
[Publications] Sato,M.: "Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBF and ETS1 in the skeletal tissues." Oncogene. 17. 1517-1525 (1998)
[Publications] Kanno,T.: "Intrinsic transcriptional activation/inhibition domains of the PEBP2/CBF α subunit revealed in the presence of the β subunit." Mol.Cell.Biol.18. 2444-2454 (1999)
[Publications] Ahn,M.-Y.: "Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dc13 by car-2,a mammalian homolog of Drosophila seven-up,and a chumeric leukemogenic gene,AML1/ETO(MTG8)." Proc.Natl.Acad.Sci.USA. 95. 1812-1817 (1998)

1998 Fiscal Year Annual Research Report

転写因子PEBP2の構造異常による白血病発症の機序

Principal Investigator

伊藤 嘉明 京都大学, ウイルス研究所, 教授 (80004612)

Research Products

[Publications] Yagi,R.: "A WW domain-containing Yes-associated protein(YAP)is a novel transcriptional co-activator." EMBO J.(in press).

[Publications] Kohzaki,H.: "Block of granulocytic differentiation of 32Dc13 cells by AML1/ETO(MTG8)but not by highly expressed Bcl-2." Oncogne. (in press).

[Publications] Li,J.: "Smad2 overexpression enhances Smad4 gene expression and suppresses CBFA1 gene expression on osteoblastic osteosarcoma ROSI7/2.8 cells." J.Biological Chem.273. 31009-31015 (1998)

[Publications] Okada,H.: "AML1(-/-embryos so not express certain hematopoiesis-related gene transcripts including those of the PUI gene." Oncogene. 17. 2287-2293 (1998)

[Publications] Kogan,S.: "The PEBP2βMYH11 fusion created by Inv(16)(p13;q22)in myeloid leukemia impairs neutrophil maturation and contributes to granulocvtic dysplasia." Proc.Natl.Acad.Sci.USA. 95. 11863-11868 (1998)

[Publications] Kim,W.-Y.: "Mutual activation of Ets-1 and AML1 DNA binding by direct interaction of their autoinhibitory domains." EMBOJ.18. 1609-1620 (1999)

[Publications] Osato,M.: "Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias." Blood. (in press).

[Publications] Tanaka,Y.: "The chimeric protein,PEBP2β/CBFβ-S,SMMHC,disorganizes cytoplasmic stress fibers and inhibits transcriptional activation." Oncogene. 17. 699-708 (1998)

[Publications] Kanno T.: "Cytoplasmic sequestration of the polyomavirus enhapcer binding protein 2(PEBP2)/core binding factor a(CBFa)subunit by the leukemia-related PEBP2/CBFβーSMMHC fusion protein inhibits PEBP2/CBF-Mediated transactivation." Mol.Cell.Biol.18. 4252-4261 (1998)

[Publications] Chen,L.-F.: "The capacity of PEBP2αB(AML1/Cbfa2)to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix." Mol.Cell.Biol.18. 4165-4176 (1998)

[Publications] Tsuji,K.: "Expression of the PEBP2αA/AML3/CBFA1 genes is Regulated by BMP4/7 heterodimer and its overexpression suppresses type I collagen and osteocalcin gene expression in osteoblastic and nonosteoblastic mesenchymal cells." Bone. 22. 87-92 (1998)

[Publications] Ji,C.: "CBFa(AML/PEBP2)-related elements in the TGF-b type I receptor promoter and expression with osteoblast differentiation." J.Cell.Biochem.69. 353-363 (1998)

[Publications] Sato,M.: "Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBF and ETS1 in the skeletal tissues." Oncogene. 17. 1517-1525 (1998)

[Publications] Kanno,T.: "Intrinsic transcriptional activation/inhibition domains of the PEBP2/CBF α subunit revealed in the presence of the β subunit." Mol.Cell.Biol.18. 2444-2454 (1999)

[Publications] Ahn,M.-Y.: "Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dc13 by car-2,a mammalian homolog of Drosophila seven-up,and a chumeric leukemogenic gene,AML1/ETO(MTG8)." Proc.Natl.Acad.Sci.USA. 95. 1812-1817 (1998)

伊藤嘉明京都大学, ウイルス研究所, 教授 (80004612)