1998 年度実績報告書

MAD関連遺伝子の構造決定と機能解析

研究課題

研究課題/領域番号	09470244
研究機関	群馬大学
研究代表者	竹之下誠一群馬大学, 医学部, 助教授 (10167489)
研究分担者	志村龍男群馬大学, 医学部, 教務員 (00282393) 浅尾高行群馬大学, 医学部, 講師 (40212469) 宮園浩平癌研究会, 附属研究所・生化学部, 部長 (90209908)
キーワード	TGF-β / Smad / 癌抑制遺伝子 / 増殖因子 / 遺伝子診断
研究概要	1. long distance sequencer methodを駆使することによって、Smad3遺伝子の構造(exon-intron構造)を決定し、Genbankに登録した(EMBL/GenBank Data Libraries under Accession Nos.AF025293 to AF025300)。Smad3遺伝子は9箇所のエクソンでコードされており、エクソンとイントロン境界領域はSmad2と完全に一致し、昨年報告した様にSmad3様のSmad2が存在することも確認できた。 2. 様々な癌組織において、全コード領域での変異の検索を進めてきたが、これまでに、癌組織でのLOHは確認されているが、Smad3遺伝子の変異は同定されていない。しかし、胃癌、大腸癌などで、Smad3は2箇所にpolymorphismが認められた。一箇所はexon2のCTG(103L)→CTA(103L)でアミノ酸は変化しない。もう一箇所はexon3でATC(170I)→GTC(170V)とアミノ酸も置換していた。しかし、イソロイシンとバリンは近縁のアミノ酸なのでこのアミノ酸置換は大きな影響を与えない可能性がある。 3. 我々は、今村らの報告したマウスSmad6の塩基配列をもとに、ヒトSmad6のcDNA、ゲノム構造を決定した。Vogelsteinらが最初に単離したSmad6のcDNAと、エクソン2以下は共通であったが、エクソン1は異なっていた。彼らのエクソン1は、ゲノム上Smad6の近傍に存在し、さらに、エクソン-イントロンのconsensus sequenceでスプライシングを受け、エクソン2につながっていることより、Smad6の本来のプロモーター以外から転写された変異体であると考えられる。またSmad6遺伝子は、4箇所のエクソンでコードされていた。

研究成果
(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] Kawate S,et al.: "Mutation analysis of transforming growth factor beta type II receptor,Smad2,and Smad4 in hepatocelular carcinoma." Int J Oncol.14(1):. 127-131 (1999)
[文献書誌] Guo RJ,et al.: "Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta typeII receptor gene in sporadic human gastric cancer." Carcinogenesis. 19(9):. 1539-1544 (1998)
[文献書誌] Takenoshita S,et al.: "Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers." Carcinogenesis. 19(5):. 803-807 (1998)
[文献書誌] Shitara Y,et al.: "Mutation of the transforming growth factor-beta type II receptor gene is a rare event in Human sporadic gastric carcinomas." Int J Oncol. 12(5):. 1061-1065 (1998)
[文献書誌] Yasumi K,et al.: "Transforming growth factor beta type II receptor(TGF beta RII)mutation in gastric lymphoma without mutator phenotype." Pathol Int. 48(2):. 134-137 (1998)
[文献書誌] Horie K,et al.: "Lack of transforming growth factor-beta type II receptor expression in human retinoblastoma cells." J Cell Physiol. 175(3):. 305-313 (1998)
[文献書誌] Takenoshita S,et al.: "Absence of mutations in the analysisi of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers." Oncol Rep. 5(2). 367-371 (1998)
[文献書誌] Takenoshita S,et al.: "Absence of mutation in the analysisi of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic humangastric cancer using genomic DNA and intron primers." Oncol Rep. 5(1). 77-80 (1998)
[文献書誌] Takenoshita S,et al.: "Characterizatiおn of the MADH2/Smad2 gene,a human Mad homolog responsible for the transforming growth factor-beta and actimin signal transduction pathway." Genomics. 15;48(1). 1-11 (1998)
[文献書誌] Tani M,et al.: "Genomic structure and chromosomal localization of the mouse Ogg1 gene that is involved in the repair of 8-hydroxyguanine in DNA damage." Mamm Genome. 9(1). 32-37 (1998)
[文献書誌] Nakajima Y,et al.: "Immunolocalization of latent transforming growth factor-β binding protein-1(LTBP1)during mouse development:possible roles in epithelial and messenchymal cytodifferentitation." Cell Tissue Res. 295. 257-267 (1999)
[文献書誌] Yanagisawa J,et al.: "Convergence of transforming growth factor-β and vitamin D signaling pathways on SMAD transcriptional coactivators." Science. 283. 1317-1321 (1999)
[文献書誌] Kim IY,et al.: "Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues." Clin Cancer Res. 2(8). 1255-1261 (1996)
[文献書誌] Nishihara A,et al.: "Role of p300,a transcriptional coactivator,in signalling of TGF-beta." Genes Cells. 3(9). 613-623 (1998)
[文献書誌] Li J,et al.: "Smad2 over expression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells." J Biol Chem. 20;273(47). 31009-31015 (1998)
[文献書誌] Goto D,et al.: "A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3,and has a dominant negative effect on TGF-beta signals." FEBS Lett.3;430(3). 201-204 (1998)
[文献書誌] Kawabata M,et al.: "Smad proteins exist as monomers in vivo and undergo homo-and hetero-oligomerization upon activation by serine/threonine kinase receptors." EMBOJ. 15;17(14). 4056-4065 (1998)
[文献書誌] Takeda K,et al.: "Identification of a novel bone morphogenetic protein-responsive gene that may function as a noncoding RNA." J Biol Chem. 3;273(27). 17079-17085 (1998)
[文献書誌] Shimizu A,et al.: "Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line." Genes Cells. 3(2). 125-134 (1998)
[文献書誌] Lu SL et al.: "HNPCC associated with germline mutation in the TGF-beta type II receptor gene." Nat Genet. 19(1). 17-18 (1998)

1998 年度 実績報告書

MAD関連遺伝子の構造決定と機能解析

研究代表者

竹之下 誠一 群馬大学, 医学部, 助教授 (10167489)

研究成果

[文献書誌] Kawate S,et al.: "Mutation analysis of transforming growth factor beta type II receptor,Smad2,and Smad4 in hepatocelular carcinoma." Int J Oncol.14(1):. 127-131 (1999)

[文献書誌] Guo RJ,et al.: "Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta typeII receptor gene in sporadic human gastric cancer." Carcinogenesis. 19(9):. 1539-1544 (1998)

[文献書誌] Takenoshita S,et al.: "Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers." Carcinogenesis. 19(5):. 803-807 (1998)

[文献書誌] Shitara Y,et al.: "Mutation of the transforming growth factor-beta type II receptor gene is a rare event in Human sporadic gastric carcinomas." Int J Oncol. 12(5):. 1061-1065 (1998)

[文献書誌] Yasumi K,et al.: "Transforming growth factor beta type II receptor(TGF beta RII)mutation in gastric lymphoma without mutator phenotype." Pathol Int. 48(2):. 134-137 (1998)

[文献書誌] Horie K,et al.: "Lack of transforming growth factor-beta type II receptor expression in human retinoblastoma cells." J Cell Physiol. 175(3):. 305-313 (1998)

[文献書誌] Takenoshita S,et al.: "Absence of mutations in the analysisi of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers." Oncol Rep. 5(2). 367-371 (1998)

[文献書誌] Takenoshita S,et al.: "Absence of mutation in the analysisi of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic humangastric cancer using genomic DNA and intron primers." Oncol Rep. 5(1). 77-80 (1998)

[文献書誌] Takenoshita S,et al.: "Characterizatiおn of the MADH2/Smad2 gene,a human Mad homolog responsible for the transforming growth factor-beta and actimin signal transduction pathway." Genomics. 15;48(1). 1-11 (1998)

[文献書誌] Tani M,et al.: "Genomic structure and chromosomal localization of the mouse Ogg1 gene that is involved in the repair of 8-hydroxyguanine in DNA damage." Mamm Genome. 9(1). 32-37 (1998)

[文献書誌] Nakajima Y,et al.: "Immunolocalization of latent transforming growth factor-β binding protein-1(LTBP1)during mouse development:possible roles in epithelial and messenchymal cytodifferentitation." Cell Tissue Res. 295. 257-267 (1999)

[文献書誌] Yanagisawa J,et al.: "Convergence of transforming growth factor-β and vitamin D signaling pathways on SMAD transcriptional coactivators." Science. 283. 1317-1321 (1999)

[文献書誌] Kim IY,et al.: "Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues." Clin Cancer Res. 2(8). 1255-1261 (1996)

[文献書誌] Nishihara A,et al.: "Role of p300,a transcriptional coactivator,in signalling of TGF-beta." Genes Cells. 3(9). 613-623 (1998)

[文献書誌] Li J,et al.: "Smad2 over expression enhances Smad4 gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells." J Biol Chem. 20;273(47). 31009-31015 (1998)

[文献書誌] Goto D,et al.: "A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3,and has a dominant negative effect on TGF-beta signals." FEBS Lett.3;430(3). 201-204 (1998)

[文献書誌] Kawabata M,et al.: "Smad proteins exist as monomers in vivo and undergo homo-and hetero-oligomerization upon activation by serine/threonine kinase receptors." EMBOJ. 15;17(14). 4056-4065 (1998)

[文献書誌] Takeda K,et al.: "Identification of a novel bone morphogenetic protein-responsive gene that may function as a noncoding RNA." J Biol Chem. 3;273(27). 17079-17085 (1998)

[文献書誌] Shimizu A,et al.: "Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line." Genes Cells. 3(2). 125-134 (1998)

[文献書誌] Lu SL et al.: "HNPCC associated with germline mutation in the TGF-beta type II receptor gene." Nat Genet. 19(1). 17-18 (1998)

1998 年度実績報告書

竹之下誠一群馬大学, 医学部, 助教授 (10167489)