2003 Fiscal Year Annual Research Report

ジーンターゲティングによるがん関連遺伝子の機能解析

Research Project

Project/Area Number	12213009
Research Institution	Tohoku University
Principal Investigator	野田哲生東北大学, 大学院・医学系研究科, 教授 (10183550)
Co-Investigator(Kenkyū-buntansha)	鈴木聡秋田大学, 医学部, 教授 (10311565)
Keywords	Patched / βカテニン / APC / PTEN
Research Abstract	本年度は、肝細胞の癌化におけるWntシグナル関連遺伝子および、Pten遺伝子の機能の解析に大きな進展が見られた。肝細胞特異的にApc遺伝子を不活化したマウスでは、Wntシグナルのメディエーターであるβcateninの蓄積が観察され、さらに肝細胞の腫大を伴う肝臓の肥大が観察された。このマウスをさらに、本研究において作成したβcateninのコンディショナルノックアウトマウスと交配したところ、Apc遺伝子のみを不活化した際に観察された上記の肝臓の異常は全て消失し、マウスは完全に健康となり、腫瘍の発生も観察されなかった。これらのことから、Apc遺伝子は肝細胞においても、βcateninを分解することにより、Wntシグナルを負に制御していることが明らかとなった。一方、やはりWntシグナルの負の制御因子と考えられているAxin遺伝子の肝細胞特異的な不活化のも成功したが、このマウスの肝臓ではβcateninの蓄積を始めとする組織学的異常は観察されず、肝細胞の発生と維持におけるAxin遺伝子の機能は明らかにはならなかった。一方、PTEN遺伝子の機能解析のため肝細胞特異的PTEN欠損マウスを作製したところ、著明な肝腫大と中性脂肪が蓄積し、非アルコール性脂肪性肝炎(NASH)を呈した。これら肝細胞には、脂肪細胞特異的な遺伝子発現が認められた。その他に脂肪酸合成や脂肪酸?酸化に関与する遺伝子群の発現が亢進し、これらはPPAR-gammaやSREBP1cの発現の亢進によるものと考えられた。また、これらマウスは約40週までにその半数に、約75週までには全例でアデノーマを呈した。さらに約75週までにこれらのアデノーマの2/3に肝癌を発症した。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] T.Noda, (他4名): "Distinct macroscopic structures developed from solutions of chemical compounds and periodic proteins."EMBO Rep.. 4(2). 148-153 (2003)
[Publications] T.Noda, (他3名): "Translated products of tandem microgene repeats exhibit diverse properties also seen in natural proteins."Protein.Eng.. 16(1). 57-63 (2003)
[Publications] T.Noda, (他15名): "Mice lacking a transcriptional corepressor Tob are predisposed to cancer."Genes Dev.. 17(10). 1201-1206 (2003)
[Publications] T.Noda, (他9名): "Crucial roles of Brn1 in distal tubule formation and function in mouse kidney."Development.. 130(19). 4751-4759 (2003)
[Publications] T.Noda, (他5名): "Characterization of Folding Pathways of the Type-1 and Type-2 Periplasmic Binding Proteins MglB and ArgT."J.Biochem.. 133(3). 371-376 (2003)
[Publications] T.Noda, (他5名): "Cell proliferation in liver of Mmh/Ogg1-deficient mice enhances mutation frequency because of the presence of 8-hydroxyguanine in DNA."Cancer Res.. 63(14). 4287-4292 (2003)
[Publications] T.Noda, ((他3名): "ARF tumor suppressor induces mitochondria-dependent apoptosis by modulation of mitochondrial Bcl-2 family proteins."J.Biol.Chem.. 278(30). 27888-27895 (2003)
[Publications] T.Noda, (他1名): "Transposition of To12 element, an Ac-like element from the Japanese medaka fish Oryzias latipes, in mouse embryonic stem cells."Genetics.. in press.. (2004)
[Publications] T.Noda, (他10名): "Combined effects of prostaglandin E receptor subtype EP_1 and subtype, EP_4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice."Cancer Sci.. 94(7). 618-621 (2003)
[Publications] T.Noda, (他14名): "PKCI in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity."J.Clin.Invest.. 112(6). 935-944 (2003)
[Publications] T.Noda, (他4名): "Tracking mouse visual pathways with WGA transgene."Eur.J.Neurosci.. 18(10). 2910-2914 (2003)
[Publications] A.Suzuki, (他8名): "Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination."J.Exp.Med. 197(5). 657-667 (2003)
[Publications] A.Suzuki, (他12名): "Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation."Cancer Res.. 63(3). 674-681 (2003)
[Publications] A.Suzuki, (他10名): "Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten."Proc.Natl.Acad.Sui.USA.. 28(1). 11-21 (2003)
[Publications] A.Suzuki, (他9名): "Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production."Development.. 130(8). 1691-1700 (2003)
[Publications] A.Suzuki, (他7名): "PI3-kinase-medeated activation of Cofilin phosphatase Slingshot-1L controls Inslin-induced membrane protrusion."J.Biol.Chem.. 279(8). 7193-7198 (2003)

2003 Fiscal Year Annual Research Report

ジーンターゲティングによるがん関連遺伝子の機能解析

Principal Investigator

野田 哲生 東北大学, 大学院・医学系研究科, 教授 (10183550)

Research Products

[Publications] T.Noda, (他4名): "Distinct macroscopic structures developed from solutions of chemical compounds and periodic proteins."EMBO Rep.. 4(2). 148-153 (2003)

[Publications] T.Noda, (他3名): "Translated products of tandem microgene repeats exhibit diverse properties also seen in natural proteins."Protein.Eng.. 16(1). 57-63 (2003)

[Publications] T.Noda, (他15名): "Mice lacking a transcriptional corepressor Tob are predisposed to cancer."Genes Dev.. 17(10). 1201-1206 (2003)

[Publications] T.Noda, (他9名): "Crucial roles of Brn1 in distal tubule formation and function in mouse kidney."Development.. 130(19). 4751-4759 (2003)

[Publications] T.Noda, (他5名): "Characterization of Folding Pathways of the Type-1 and Type-2 Periplasmic Binding Proteins MglB and ArgT."J.Biochem.. 133(3). 371-376 (2003)

[Publications] T.Noda, (他5名): "Cell proliferation in liver of Mmh/Ogg1-deficient mice enhances mutation frequency because of the presence of 8-hydroxyguanine in DNA."Cancer Res.. 63(14). 4287-4292 (2003)

[Publications] T.Noda, ((他3名): "ARF tumor suppressor induces mitochondria-dependent apoptosis by modulation of mitochondrial Bcl-2 family proteins."J.Biol.Chem.. 278(30). 27888-27895 (2003)

[Publications] T.Noda, (他1名): "Transposition of To12 element, an Ac-like element from the Japanese medaka fish Oryzias latipes, in mouse embryonic stem cells."Genetics.. in press.. (2004)

[Publications] T.Noda, (他10名): "Combined effects of prostaglandin E receptor subtype EP_1 and subtype, EP_4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice."Cancer Sci.. 94(7). 618-621 (2003)

[Publications] T.Noda, (他14名): "PKCI in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity."J.Clin.Invest.. 112(6). 935-944 (2003)

[Publications] T.Noda, (他4名): "Tracking mouse visual pathways with WGA transgene."Eur.J.Neurosci.. 18(10). 2910-2914 (2003)

[Publications] A.Suzuki, (他8名): "Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination."J.Exp.Med. 197(5). 657-667 (2003)

[Publications] A.Suzuki, (他12名): "Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation."Cancer Res.. 63(3). 674-681 (2003)

[Publications] A.Suzuki, (他10名): "Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten."Proc.Natl.Acad.Sui.USA.. 28(1). 11-21 (2003)

[Publications] A.Suzuki, (他9名): "Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production."Development.. 130(8). 1691-1700 (2003)

[Publications] A.Suzuki, (他7名): "PI3-kinase-medeated activation of Cofilin phosphatase Slingshot-1L controls Inslin-induced membrane protrusion."J.Biol.Chem.. 279(8). 7193-7198 (2003)

野田哲生東北大学, 大学院・医学系研究科, 教授 (10183550)