2007 Fiscal Year Final Research Report Summary
Analysis of Immunodeficiencies with defective DNA damage response
| Project/Area Number |
18591184
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
MORIO Tomohiro Tokyo Medical and Dental University, Graduate School, 准教授 (30239628)
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| Co-Investigator(Kenkyū-buntansha) |
森尾 友宏 東京医科歯科大学, 大学院・医歯学総合研究科 (30239628)
MINEGISHI Yoshiyuki Tokyo Medical and Dental University, Graduate School, 准教授 (10343154)
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| Project Period (FY) |
2006 – 2007
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| Keywords | DNA damage response / Immunodeficiency / Malignancy / Ataxia telangiectasia / Artemis / KU70 / 80 / DNA ligase IV / Cernunnos |
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| Research Abstract |
We sought to analyze molecular mechanism of immunodeficiency caused by defective DNA damage response working on cells from disorders including ataxia-telangiectasia (AT), Artemis deficiency, and Nijmegen breakage syndrome (NBS1 deficiency).
We have so far revealed that S645 of Artemis is phosphorylated by ATM upon DNA damaging reagent. Through this study, we have shown 70-kDa molecule is associated with Artemis and controls stability of Artemis. The interaction requires phosphorylation of Artemis, but the site is not in the hitherto-known region. A new role of Artemis was also demonstrated. Endonuclease activity of Artemis was shown to be required for double strand DNA break when DNA replication is stalled in a ragging strand. This process was dependent on ATM. Further investigation is currently in progress.
DNA damage response (DDR) is absolutely required for diversification of immune receptors; and disrupted DDR during the process leads to chromosomal aberration. We analyzed involvement of the DDR molecules in tumorigenesis, and found that DDR is activated in pre-malignant stage. The loss of DDR led to malignant transformation of the cells with mutation in p53 in some cases (Leukemia 2006).
ATM and Ku70/80 were shown to be degraded upon oxidative stress leading to cellular apoptosis (Ann NY Acad Sci 2006, Int J Biochem Cell Biol. 2008)。 The cells escaped from apoptosis may lead to acquisition of chromosomal aberration.
We diagnosed 14 patients with AT, 2 DNA ligase IV deficiency, 2 Mre11deficiency (ATLD) and one Cernunnos deficiency. Finally, we carried out the first nation-wide survey for AT. We observed phenotypic variety between sibling cases with AT. Hyper-IgM was noted in 10% of the patients indicating involvement of ATM in class switch recombination.
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Research Products
(52 results)
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[Journal Article] Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals.2008
Author(s)
Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS, Kitamura D, Kurosaki T, Ellmeier W, Takayanagi H.
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Journal Title
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals2008
Author(s)
Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS, Kitamura D, Kurosaki T, Ellmeier W, Takayanagi H.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen.2007
Author(s)
Tono C, Takahashi Y, Terui K, Sasaki S, Kamio T, Tandai S, Sato T, Kudo K, Toki T, Tachibana N, Yoshioka T, Nakahata T, Morio T, Nishikomori R, Ito E.
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Journal Title
Bone Marrow Transplant. 39
Pages: 801-4
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Clonotypic analysis of T cell reconstitution after haematopoietic stem cell transplantation (HSCT) in patients with severe combined immune-deficiency.2007
Author(s)
Okamoto H, Arii C, Shibata F, Toma T, Wada T, Inoue M, Tone Y, Kasahara Y, Koizumi S, Kamachi Y, Ishida Y, Inagaki J, Kato M, Morio T, Yachie A.
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Journal Title
Clin. Exp. Immunol 148
Pages: 450-60
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Hematopoietic Stem Cell-Engrafted NOD/SCID/IL2R null Mice Develop Human Lymphoid System and Induce Long-Lasting HIV-1 Infection with Specific Humoral Immune Responses.2007
Author(s)
Watanabe S., Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y, Dewan Md Z, Yu Z, Ito M, Morio T, Shimizu N, Honda M, and Yamamoto N.
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Journal Title
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Knockdown of XAB2 enhances All-Trans Retinoic Acid-Induced Cellular Differentiation in All-Trans Retinoic Acid-Sensitive and-Resistant Cancer Cells.2007
Author(s)
Ohnuma-Ishikawa K, Morio T, Yamada T, Sugawara Y, Ono M, Nagasawa M, Yasuda A, Morimoto C, Ohnuma K, Dang NH, Hosoi H, Verdin E, and Mizutani S.
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Journal Title
Cancer Res. 67
Pages: 1019-29
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen2007
Author(s)
Tono C, Takahashi Y, Terui K, Sasaki S, Kamio T, Tandai S, Sato T, Kudo K, Toki T, Tachibana N, Yoshioka T, Nakahata T, Morio T, Nishikomori R, Ito E.
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Journal Title
Bone Marrow Transplant 39
Pages: 801-4
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Clonotypic analysis of T cell reconstitution after haematopoietic stem cell transplantation(HSCT) in patients with severe combined immunodeficiency. Clin. Exp2007
Author(s)
Okamoto H, Arii C, Shibata F, Toma T, Wada T, Inoue M, Tone Y, Kasahara Y, Koizumi S, Kamachi Y, Ishida Y, Inagaki J, Kato M, Morio T, Yachie A.
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Journal Title
Immunol 148
Pages: 450-60
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hematopoietic Stem Cell-Engrafted NOD/SCID/IL2R□^<null> Mice Develop Human Lymphoid System and Induce Long-Lasting HIV-1 Infection with Specific Humoral Immune Responses2007
Author(s)
Watanabe S., Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y, Dewan Md Z, Yu Z, Ito M, Morio T, Shimizu N, Honda M, and Yamamoto N.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Knockdown of XAB2 enhances All-Trans Retinoic Acid-Induced Cellular Differentiation in All-Trans Retinoic Acid-Sensitive and -Resistant Cancer2007
Author(s)
Ohnuma-Ishikawa K, Morio T, Yamada T, Sugawara Y, Ono M, Nagasawa M, Yasuda A, Morimoto C, Ohnuma K, Dang NH, Hosoi H, Verdin E, and Mizutani S.
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Journal Title
Cells. Cancer Res 67
Pages: 1019-29
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The First Infant Case With Hepatosplenic gammadelta T-cell Lymphoma After Acute Disseminated Encephalomyelitis (ADEM)-like Exacerbation.2006
Author(s)
Koga SY, Kumaki S, Ichinohasama R, Munakata M, Haginoya K, Ohashi Y, Tanaka Y, Sakamoto O, Minegishi M, Morio T, Iinuma K, Tsuchiya S.
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Journal Title
JPediatr Hematol Oncol. 28
Pages: 741-45
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.2006
Author(s)
Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H.
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Journal Title
Immunity. 25
Pages: 745-55
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] The First Infant Case With Hepatosplenic gammadelta T-cell Lymphoma After Acute Disseminated Encephalomyelitis(ADEM)-like Exacerbation2006
Author(s)
Koga SY, Kumaki S, Ichinohasama R, Munakata M, Haginoya K, Ohashi Y, Tanaka Y, Sakamoto O, Minegishi M, Morio T, Iinuma K, Tsuchiya S.
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Journal Title
J Pediatr Hematol Oncol 28
Pages: 741-45
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity2006
Author(s)
Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H.
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Journal Title
Immunity 25
Pages: 745-755
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Norio Shimizu Follicular dendritic cells(FDC), expressing ependymin related protein(ERP) and GM1, are of pluripotent mesencymal stem cells(pMSC) interfacing immune system and nerous system2007
Author(s)
Kazuo Terashima, Yoko Mochimaru, Ken Watanabe, Tomohiro Morio, Ichiro Matsumoto, Satoru Watanabe, Kenji Ooba, Midori Taruishi, Chieko Kishi, Naoki Yamamoto
Organizer
Biochemistry and Molecular Biology
Place of Presentation
Yokohama
Year and Date
20071211-15
Description
「研究成果報告書概要(欧文)」より
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