Hematopoietic stem cell maintenance by Mediator transcriptional coregulator complex

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591388
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kobe University
• Principal Investigator: ITO Mitsuhiro 神戸大学, 保健学研究科, 教授 (50362794)
• Project Period (FY): 2011 – 2013
• Keywords: FGF7 / hematopoietic niche / stromal cells / MED1 / Mediator

Research Abstract

FGF7 expression was attenuated in mouse embryonic fibroblasts (MEFs) deficient for the MED1 subunit of the Mediator transcriptional coregulator complex. When normal mouse bone marrow (BM) cells were cocultured with BM stromal cells in the presence of anti-FGF7 antibody, the growth of BM cells and the number of long-time culture-initiating cells (LTC-ICs) decreased significantly. Anti-FGF7 antibody also attenuated the proliferation and cobblestone formation of MB1 stromal cell-dependent myeloblastoma cells. The addition of recombinant FGF7 to the coculture of BM cells and Med1-/- MEFs increased BM cells and LTC-ICs. FGF7 and its cognate receptor, FGFR2IIIb, were undetectable in BM cells, but MEFs and BM stromal cells expressed both. FGF7 activated downstream targets of FGFR2IIIb in wild type MEFs, MED1 knockout MEFs, and BM stromal cells. Taken together, we propose that FGF7 supports HSPCs and leukemia-initiating cells indirectly via FGFR2IIIb expressed on stromal cells.

Research Products

• [Journal Article] CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function (2014)
  • Author(s): S. Mizuta, T. Minami, H. Fujita, C. Kaminaga, K. Matsui, R. Ishino, A. Fujita, K. Oda, A. Kawai, N. Hasegawa, N. Urahama, R. G. Roeder, M. Ito
  • Journal Title: Genes Cells Volume: 19 Pages: 28-51
  • DOI: 10.1111/gtc.12104
  • Peer Reviewed
• [Journal Article] FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro. (2013)
  • Author(s): R. Ishino, K. Minami, S. Tanaka, M. Nagai, K. Matsui, N. Hasegawa, R.G. Roeder, S. Asano, M. Ito
  • Journal Title: Biochem Biophys. Res. Commun Volume: 440 Pages: 125-131
  • DOI: 10.1016/j.bbrc.2013.09.044
  • Peer Reviewed
• [Journal Article] Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropinβgene promoter (2013)
  • Author(s): K. Matsui, K. Oda, S. Mizuta, R. Ishino, N. Urahama, N. Hasegawa, R.G. Roeder, M. Ito
  • Journal Title: Biochem Biophys Res Commun Volume: 440 Pages: 184-189
  • DOI: 10.1016/j.bbrc.2013.09.061
  • Peer Reviewed
• [Journal Article] Expansion of PD-1-Positive Effector CD4 T Cells in an Experimental Model of SLE : Contribution to the Self-Organized Criticality Theory (2013)
  • Author(s): Y. Miyazaki, K. Tsumiyama, T. Yamane, M. Ito, S. Shiozawa
  • Journal Title: Kobe J. Med. Sci Volume: 59 Pages: 64-71
  • URL: http://www.med.kobe-u.ac.jp/journal/contents/59/E64.pdf
  • Peer Reviewed
• [Journal Article] Self-Organized Criticality Theory and the Expansion of PD-1-Positive Effector CD4 T Cells : Search for Autoantibody-Inducing CD4 T Cells (2013)
  • Author(s): Y. Miyazaki, K. Tsumiyama, T. Yamane, M. Ito, S. Shiozawa
  • Journal Title: Front. Immunol, (Print 2013) Volume: 4 Pages: 87
  • DOI: 10.3389/fimmu.2013.00087
  • Peer Reviewed
• [Journal Article] Significance of the neutrophil myeloperoxidase index in patients with atherosclerotic diseases (2012)
  • Author(s): K. Yonezawa, N. Morimoto, K. Matsui, T. Tenjin, M. Yoneda, T. Emoto, T. Sawada, T. Nomura, H. Okamoto, A. Takarada, H. Ikeda, M. Ito
  • Journal Title: Kobe J. Med. Sci Volume: 58 Pages: 128-137
  • URL: http://www.med.kobe-u.ac.jp/journal/contents/58/E128.pdf
  • Peer Reviewed
• [Journal Article] Mediator subunits MED1 and MED24 cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells (2012)
  • Author(s): N. Hasegawa, A. Sumitomo, A. Fujita, N. Aritome, S. Mizuta, K. Matsui, R. Ishino, K. Inoue, N. Urahama, J. Nose, T. Mukohara, S. Kamoshida, R. G. Roeder, M. Ito
  • Journal Title: Mol. Cell. Biol Volume: 32 Pages: 1483-1495
  • DOI: 10.1128/MCB.05245-11
  • Peer Reviewed
• [Journal Article] JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients (2011)
  • Author(s): T. Irino, M. Uemura, H. Yamane, S. Umemura, T. Utsumi, N. Kakazu, T. Shirakawa, M. Ito, T. Suzuki, K. Kinoshita
  • Journal Title: PLoS ONE Volume: 6 Pages: e22148
  • DOI: 10.1371/journal.pone.0022148
  • Peer Reviewed
• [Journal Article] Benefits of skin biopsy of senile hemangioma in intravascular large B-cell lymphoma : A case report and review of the literature
  • Author(s): Y. Adachi, M. Kosami, N. Mizuta, M. Ito, Y. Matsuoka, M. Kanata, H. Akiyama, T. Murao, M. Li, R. Ieki, S. Ikehara
  • Journal Title: Oncology Letters Volume: (in press)
  • Peer Reviewed
• [Presentation] FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro (2014)
  • Author(s): R. Ishino, S. Tanaka, K. Matsui, K. Minami, Y. Ikeuchi, M. Yano, A. Imanishi, M. Nagai, N. Hasegawa, S. Asano, M. Ito
  • Organizer: Highlights of ASH in Asia
  • Place of Presentation: Singapore, Singapore
  • Year and Date: 20140329-30
  • Invited
• [Presentation] FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro (2013)
  • Author(s): R. Ishino, K. Matsui, S. Tanaka, K. Minami, Y. Ikeuchi, M. Yano, A. Imanishi, M. Nagai, N. Hasegawa, S. Asano, M. Ito
  • Organizer: 55th Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131207-10
• [Presentation] FGF7 supports mouse hematopoietic stem and progenitor cells via FGFR2IIIb expressed on stromal cells (2013)
  • Author(s): R. Ishino, K. Minami, Y. Ikeuchi, M. Yano, A. Imanishi, S. Tanaka, K. Yonezawa, K. Matsui, S. Mizuta, S. Asano, M. Ito
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
  • Year and Date: 20131011-13
• [Presentation] Physical interaction between PPARγ2 and Mediator subunit MED1 is crucial for induced adipocyte hypertrophy (2013)
  • Author(s): M. Ito, K. Matsui, R. Ishino, N. Hasegawa, R.G. Roeder
  • Organizer: Cold Spring Harbor Laboratory Meeting, Mechanism of Eukaryotic Transcription
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 20130827-31
• [Presentation] 血液疾患と発熱 (2013)
  • Author(s): 伊藤光宏
  • Organizer: 第66回兵庫県医師会医学会, シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2013-10-20
• [Presentation] Role of Mediator subunit MED1 in nuclear receptor functions in adipogenesis (2013)
  • Author(s): R.G. Roeder, S. Iida, W. Chen, K. Matsui, R. Ishino, N. Hasegawa, M. Ito
  • Organizer: EMBO Conference, Nuclear Receptors
  • Place of Presentation: Sorrento, Italy, (基調講演)
  • Year and Date: 2013-09-06
• [Presentation] CCAR1/CoCoA-mediated recruitment of the Mediator indicates a novel pathway for GATA1 action in erythropoiesis (2012)
  • Author(s): S. Mizuta, H. Fujita, C. Kaminaga, T. Minami, K Matsui, R. Ishino, A. Fujita, K. Oda, N. Urahama, R.G. Roeder, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] FGF7 is a novel niche factor that supports hematopoietic stem/progenitor cells in the hematopoietic niche model (2012)
  • Author(s): R. Ishino, K. Minami, Y. Ikebata, Y. Ikeuchi, K. Yonezawa, K. Matsui, S. Mizuta, S. Asano, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] Increased sensitivity to insulin at obese stress in mice with defective MED1 nuclear receptor recognition motifs (2012)
  • Author(s): N. Kubota, K. Matsui, Y. Morimoto, Y. Hirohata, N. Hasegawa, R. Ishino, S. Mizuta, A. Fujita, N. Urahama, R.G. Roeder, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] CCAR1 plays as an adaptor coactivator for PPARγand MED1 function (2012)
  • Author(s): Y. Ikeuchi, K. Matsui, Y. Morimoto, N. Kubota, S. Mizuta, A. Fujita, R. Ishino, R.G. Roeder, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] Mediator subunit MED1 is a T3-dependent coactivator on nTRE of the TSHβpromoter (2012)
  • Author(s): K. Matsui, K. Oda, T. Hata, Sh. Mizuta, Y. Hirohata, R. Ishino, N. Urahama, R.G. Roeder, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] Interaction of MED1 with VDR does not determine NKT cell population (2012)
  • Author(s): Y. Hirohata, K. Matsui, N. Kubota, Y. Morimoto, R. Ishino, R.G. Roeder, S. Asano, M. Ito
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 20121211-14
• [Presentation] CCAR1/CoCoA-mediated Mediator recruitment indicates novel pathway for GATA1 action in erythropoiesis (2012)
  • Author(s): S. Mizuta, C. Kaminaga, H. Fujita, K. Matsui, R. Ishino, K. Oda, A. Fujita, N. Kubota, N. Urahama, M. Ito
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 20121019-21
• [Presentation] Level of Granzyme B expression in leukocytes may predict GVL effect after allogeneic transplantation (2012)
  • Author(s): O. Horie, K. Minami, K. Yonezawa, Y. Morimoto, Y. Ikeuchi, H. Gomyo, A. Maeda, I. Mizuno, T. Murayama, M. Ito
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 20121019-21
• [Presentation] Significance of neutrophil myeloperoxidase index in ischemic heart diseases complicated by ASO (2012)
  • Author(s): K. Yonezawa, N. Morimoto, K. Matsui, T. Tenjin, M. Yoneda, T. Emoto, T. Sawada, T. Nomura, H. Okamoto, A. Takarada, H. Ikeda, M. Ito
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 20121019-21
• [Presentation] 赤芽球分化を誘導するコアクチベーターCCAR1とCoCoAの造血組織における特異的発現 (2012)
  • Author(s): 藤田陽加、水田駿平、神永千尋、織田華澄、松井啓治、森本由紀、畑ともみ、池端夕莉、浦浜憲永、伊藤光宏
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 20121019-21
• [Presentation] Significance of the Neutrophil Myeloperoxidase Index in Patients with Ischemic Heart Diseases Complicated by Arteriosclerosis Obliterans (2012)
  • Author(s): K. Yonezawa, N. Morimoto, K. Matsui, T. Tenjin, M. Yoneda, T. Emoto, T. Sawada, T. Nomura, H. Okamoto, A. Takarada, H. Ikeda, M. Ito
  • Organizer: 25th International Symposium on Technological Innovations in Laboratory Hematology
  • Place of Presentation: Nice, France
  • Year and Date: 20120510-12
• [Presentation] Mediator subunits MED1 and MED24 cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells (2012)
  • Author(s): A. Fujita, S. Mizuta, K. Matsui, R. Ishino, T. Mukohara, S. Kamoshida, R.G. Roeder, M. Ito
  • Organizer: Keystone Symposium on Nuclear Receptor Matrix : Reloaded
  • Place of Presentation: Whistler, British Columbia, Canada
  • Year and Date: 20120415-20
• [Presentation] 血管免疫芽球性T細胞リンパ腫(AITL)が疑われた1例 (2012)
  • Author(s): 植木一仁、孝橋睦生、金田好弘、南建輔、日野拓耶、家城隆次、足立靖、伊藤光宏
  • Organizer: 第198回日本内科学会近畿地方会例会
  • Place of Presentation: 京都
  • Year and Date: 2012-09-08
• [Presentation] FGF7 promotes growth of bone marrow cells in hematopoietic niche (2011)
  • Author(s): R. Ishino, A. Sumitomo, K. Minami, S. Yamagishi, K. Yonezawa, K. Matsui, S. Mizuta, O. Horie, M. Ito
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] CCAR1はPPARとその特異的転写共役因子MED1を架橋する (2011)
  • Author(s): 松井啓治、森本由紀、池内友紀子、窪田奈々、水田駿平、藤田あずさ、石野瑠璃、Robert G. Roeder、伊藤光宏
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] GATA1特異的転写共役因子MED1を介する赤芽球分化における核内シグナル副経路の存在 (2011)
  • Author(s): 水田駿平、南智也、神永千尋、織田華澄、藤田陽加、松井啓治、石野瑠璃、住友明子、浦浜憲永、伊藤光宏
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] 転写メディエーターサブユニットMED1はTSHプロモーターでリガンド依存性および非依存性のコアクチベーターとして機能する (2011)
  • Author(s): 織田華澄、松井啓治、水田駿平、神永千尋、R.G. Roeder、伊藤光宏
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] 転写メディエーターサブユニットMED1とMED24の乳癌細胞増殖における役割 (2011)
  • Author(s): 藤田あずさ、住友明子、有留奈見、水田駿平、石野瑠璃、松井啓治、向原徹、鴨志田伸吾、伊藤光宏
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20111213-16
• [Presentation] CoCoA/CCAR1 pair-mediated recruitment of Mediator complex indicates novel pathway for the function of GATA1 in erythroid differentiation (2011)
  • Author(s): C. Kaminaga, S. Mizuta, T. Minami, K. Oda, H. Fujita, K. Matsui, R. Ishino, Sumitomo, N. Urahama, M. Ito
  • Organizer: 53rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111210-13
• [Presentation] The role of proteinase inhibitor 9 (PI-9) and granzyme B in peripheral leukocytes for GVL and GVHD after allogeneic hematopoietic stem cell transplantation (2011)
  • Author(s): O. Horie, K. Minami, K. Yonezawa, H. Gomyo, A. Maeda, I. Mizuno, T. Murayama, M. Ito
  • Organizer: 53rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: San Diego, USA
  • Year and Date: 20111210-13
• [Presentation] The role of MED1 in GATA1-mediated erythroid differentiation of K562 erythroleukemia cells (2011)
  • Author(s): S. Mizuta, T. Minami, C. Kaminaga, K. Oda, H. Fujita, K. Matsui, Sumitomo, R. Ishino, M. Ito
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 20111014-16
  • Invited
• [Presentation] FGF7 as growth-promoting niche factor for bone marrow cells (2011)
  • Author(s): R. Ishino, A. Sumitomo, K. Minami, K. Yonezawa, K. Matsui, S. Mizuta, O. Horie, M. Ito
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 20111014-16
• [Presentation] JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients (2011)
  • Author(s): K. Kinoshita, T. Irino, M. Uemura, H. Yamane, S. Umemura, T. Utsumi, N. Kakazu, T. Shirakawa, M. Ito, T. Suzuki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 20111003-05
• [Presentation] VDR-mediated osteopontin transcription plays crucial role in hematopoietic niche in concert with FGF7 (2011)
  • Author(s): R. Ishino, K. Matsui, A. Sumitomo, K. Inoue, K. Minami, S. Yamagishi, S. Mizuta, O. Horie, N. Urahama, M. Ito
  • Organizer: EMBO Conference Nuclear Receptors
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110916-20
• [Presentation] Physical interaction between PPARγand MED1 is crucial for adipose tissue homeostasis and glucose metabolism (2011)
  • Author(s): M. Ito, K. Matsui, R. Ishino, S. Mizuta, Y. Morimoto, N. Hasegawa, R. G. Roeder
  • Organizer: EMBO Conference, Nuclear Receptors
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20110916-20
• [Presentation] CCAR1-mediated recruitment of Mediator complex in GATA1-induced transcriptional activation (2011)
  • Author(s): S. Mizuta, T. Minami, C. Kaminaga, K. Oda, H. Fujita, K. Matsui, R. Ishino, A. Sumitomo, M. Ito
  • Organizer: Cold Spring Harbor Laboratory Meeting, Mechanism of Eukaryotic Transcription
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 20110830-0903
• [Remarks]
  • URL: http://www2.kobe-u.ac.jp/~itomi/