Research activity information

• Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4.

  Kana Kuronuma, Aya Yokoi, Tomoya Fukuoka, Muneaki Miyata, Akio Maekawa, Satowa Tanaka, Leo Matsubara, Chie Goto, Miki Matsuo, Hao-Wei Han, Mai Tsuruta, Haruka Murata, Hikari Okamoto, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito

  Matrix Gla protein (MGP), a modulator of the BMP-SMAD signals, inhibits arterial calcification in a Glu γ-carboxylation dependent manner but the role of MGP highly expressed in a subset of bone marrow (BM) mesenchymal stem/stromal cells is unknown. Here we provide evidence that MGP might be a niche factor for both normal and malignant myelopoiesis. When mouse BM hematopoietic cells were cocultured with mitomycin C-treated BM stromal cells in the presence of anti-MGP antibody, growth of hematopoietic cells was reduced by half, and maintenance of long-term culture-initiating cells (LTC-ICs) was profoundly attenuated. Antibody-mediated blockage of MGP also inhibited growth (by a fifth) and cobblestone formation (by half) of stroma-dependent MB-1 myeloblastoma cells. MGP was undetectable in normal hematopoietic cells but was expressed in various mesenchymal cells and was aberrantly high in MB-1 cells. MGP and bone morphogenetic protein (BMP)-4 were co-induced in stromal cells cocultured with both normal hematopoietic cells and MB-1 myeloblastoma cells in an oscillating several days-periodic manner. BMP-2 was also induced in stromal cells cocultured with normal hematopoietic cells but was barely expressed when cocultured with MB-1 cells. GST-pulldown and luciferase reporter assays showed that uncarboxylated MGP interacted with BMP-4 and that anti-MGP antibody abolished this interaction. LDN-193189, a selective BMP signaling inhibitor, inhibited growth and cobblestone formation of MB-1 cells. The addition of warfarin, a selective inhibitor of vitamin K-dependent Glu γ-carboxylation, did not affect MB-1 cell growth, suggesting that uncarboxylated MGP has a biological effect in niche. These results indicate that MGP may maintain normal and malignant hematopoietic progenitor cells, possibly by modulating BMP signals independently of Glu γ-carboxylation. Aberrant MGP by leukemic cells and selective induction of BMP-4 relative to BMP-2 in stromal cells might specify malignant niche.

  Apr. 2020, Heliyon, 6(4) (4), e03743, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Translin restricts the growth of pubertal mammary epithelial cells estrogen-independently in mice

  Leo Matsubara, Tomoya Fukuoka, Katsuko Sudo, Takako Fukunaga, Azusa Imanishi, Kana Kuronuma, Miki Matsuo, Shingo Kamoshida, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito

  Translin, a ubiquitous RNA/DNA-binding protein that forms a hetero-octamer together with Translin-associated factor X (TRAX), possesses endoribonuclease activity and plays a physiological role in restricting the size and differentiation of mesenchymal precursor cells. However, the precise role of Translin in epithelial cells remains unclear. Here, we show evidence that Translin restricts the growth of pubertal mammary epithelial cells. The mammary epithelia of Translin-null females exhibited retarded growth before puberty, but highly enhanced growth and DNA synthesis with increased ramification after the onset of puberty. Primary cultures of Translin-null mammary epithelial cells showed augmented DNA synthesis in a ligand-independent and ligand-enhanced manner. Translin-null ovariectomized mice implanted with slow-release estrogen pellets showed enhanced length and ramification of the mammary glands. Mammary epithelial growth was also observed in ovariectomized Translin-null mice implanted with placebo pellets. Luciferase reporter assays using embryonic fibroblasts from Translin-null mice showed unaltered estrogen receptor α function. These results indicate that Translin plays a physiological role in restricting intrinsic growth, beyond mesenchymal cells, of pubertal mammary epithelial cells.

  Elsevier BV, Jan. 2020, Biochemical and Biophysical Research Communications, 521(3) (3), 562 - 568, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• PML-RARα induces all-trans retinoic acid-dependent transcriptional activation through interaction with MED1.

  Tomoya Fukuoka, Asami Kawai, Taku Takahara, Mahiro Mori, Robert G Roeder, Natsumi Hasegawa, Mitsuhiro Ito

  Transcriptional activation by PML-RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML-RARα complex leads to the formation of the preinitiation complex has been unidentified. Here we demonstrate that the Mediator subunit MED1 plays an important role in the ATRA-dependent activation of the PML-RARα-bound promoter. Luciferase reporter assays showed that PML-RARα induced significant transcription at pharmacological doses (1 μM) of ATRA; however, this was submaximal and equivalent to the level of transcription driven by intact RARα at physiological doses (1 nM) of ATRA. Transcription depended upon the interaction of PML-RARα with the two LxxLL nuclear receptor recognition motifs of MED1, and LxxLL→LxxAA mutations led to minimal transcription. Mechanistically, MED1 interacted ATRA-dependently with the RARα portion of PML-RARα through the two LxxLL motifs of MED1. These results suggest that PML-RARα initiates ATRA-induced transcription through its interaction with MED1.

  Jun. 2019, Transcription, 10(3) (3), 147 - 156, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Translin modulates mesenchymal cell proliferation and differentiation in mice

  Yukiko Ikeuchi, Azusa Imanishi, Katsuko Sudo, Takako Fukunaga, Aya Yokoi, Leo Matsubara, Chie Goto, Tomoya Fukuoka, Kana Kuronuma, Ruri Kono, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito

  Elsevier B.V., Sep. 2018, Biochemical and Biophysical Research Communications, 504(1) (1), 115 - 122, English

  Scientific journal


• Periostin supports hematopoietic progenitor cells and niche-dependent myeloblastoma cells in vitro

  Satowa Tanaka, Akio Maekawa, Leo Matsubara, Azusa Imanishi, Masaya Yano, Robert G. Roeder, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito

  Sep. 2016, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 478(4) (4), 1706 - 1712, English

  [Refereed]

  Scientific journal


• CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function

  Shumpei Mizuta, Tomoya Minami, Haruka Fujita, Chihiro Kaminaga, Keiji Matsui, Ruri Ishino, Azusa Fujita, Kasumi Oda, Asami Kawai, Natsumi Hasegawa, Norinaga Urahama, Robert G. Roeder, Mitsuhiro Ito

  Jan. 2014, GENES TO CELLS, 19(1) (1), 28 - 51, English

  [Refereed]

  Scientific journal


• Mediator subunit MED1 is a T3-dependent and T3-independent coactivator on the thyrotropin beta gene promoter

  Keiji Matsui, Kasumi Oda, Shumpei Mizuta, Ruri Ishino, Norinaga Urahama, Natsumi Hasegawa, Robert G. Roeder, Mitsuhiro Ito

  Oct. 2013, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 440(1) (1), 184 - 189, English

  [Refereed]

  Scientific journal


• FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro

  Ruri Ishino, Kaori Minami, Satowa Tanaka, Mami Nagai, Keiji Matsui, Natsumi Hasegawa, Robert G. Roeder, Shigetaka Asano, Mitsuhiro Ito

  Oct. 2013, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 440(1) (1), 125 - 131, English

  [Refereed]

  Scientific journal


• Mediator Subunits MED1 and MED24 Cooperatively Contribute to Pubertal Mammary Gland Development and Growth of Breast Carcinoma Cells

  Natsumi Hasegawa, Akiko Sumitomo, Azusa Fujita, Nami Aritome, Shumpei Mizuta, Keiji Matsui, Ruri Ishino, Kana Inoue, Norinaga Urahama, Junko Nose, Toru Mukohara, Shingo Kamoshida, Robert G. Roeder, Mitsuhiro Ito

  Apr. 2012, MOLECULAR AND CELLULAR BIOLOGY, 32(8) (8), 1483 - 1495, English

  [Refereed]

  Scientific journal


• The transcriptional mediator subunit MED1/TRAP220 in stromal cells is involved in hematopoietic stem/progenitor cell support through osteopontin expression.

  Akiko Sumitomo, Ruri Ishino, Norinaga Urahama, Kana Inoue, Kenji Yonezawa, Natsumi Hasegawa, Osamu Horie, Hiroshi Matsuoka, Toru Kondo, Robert G Roeder, Mitsuhiro Ito

  MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators, such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow (BM) cells cocultured with MED1 knockout (Med1(-/-)) mouse embryonic fibroblasts (MEFs) was significantly suppressed compared to the control. Furthermore, the number of long-term culture-initiating cells (LTC-ICs) was attenuated for BM cells cocultured with Med1(-/-) MEFs. The vitamin D receptor (VDR)- and Runx2-mediated expression of OPN, as well as Mediator recruitment to the Opn promoter, was specifically attenuated in the Med1(-/-) MEFs. Addition of OPN to these MEFs restored the growth of cocultured BM cells and the number of LTC-ICs, both of which were attenuated by the addition of the anti-OPN antibody to Med1(+/+) MEFs and to BM stromal cells. Consequently, MED1 in niche appears to play an important role in supporting HSPCs by upregulating VDR- and Runx2-mediated transcription on the Opn promoter.

  Oct. 2010, Molecular and cellular biology, 30(20) (20), 4818 - 27, English, International magazine

  Scientific journal


• Involvement of Transcriptional Mediator Subunit TRAP220/MED1 in Action of Niche Cells to Support Hematopoietic Stem/Progenitor Cells.

  Kana Inoue, Akiko Sumitomo, Natsumi Hasegawa, Ayuko Kasai, Kenji Yonezawa, Norinaga Urahama, Mitsuhiro Ito

  Nov. 2008, BLOOD, 112(11) (11), 1225 - 1225, English

  [Refereed]

  Research society

• Nuclear receptor binding capacity of MED1 is required for maintaining body temperature at cold environment

  平野希依, Kie Hirano, 物延沙耶, Saya Mononobe, Natsumi Hasegawa, Mitsuhiro Ito

  第40回日本分子生物学会, 2017, Japanese, Domestic conference

  Poster presentation


• MED1 regulates mobilization of IL-33 indused type 2 innate lymphoid cells

  ERI ADACHI, NATSUMI HASEGAWA, 前川茜(Akane Maekawa, 物延沙耶, Saya Mononobe, 平野希依(Kie Hirano, 後藤千恵(Chie Goto, 横井彩(Aya Yokoi, 黒沼加菜, Kana Kuronuma, MITSUHIRO ITO

  第40回日本分子生物学会, 2017, Japanese, Domestic conference

  Poster presentation


• Metabolic markers expressed in mice where MED1 nuclear receptor recognition motifs are defeated

  SAYA MONONOBE, KIE HIRANO, ERI ADACHI, YUKI MINEMATSU, MIKI MATSUO, KASUMI GOWA, MISAKI HATTORI, KANA KURONUMA, NATSUMI HASEGAWA, MITSUHIRO ITO

  第40回日本分子生物学会, 2017, Japanese, Domestic conference

  Poster presentation


• Mediator may be involved in transcriptional activation through N-terminal activation domain of GATA1

  福岡知也, Tomoya Fukuoka, 松尾美希(Miki Matsuo, 後和佳澄, Kasumi Gowa, 森真洋(Mahiro Mori, 河合麻美, Asami Kawai, 水田駿平, Shunpei Mizuta, 峰松侑希, Yuki Minematsu, 服部美咲, Misaki Hattori, HASEGAWA NATSUMI, Mitsuhiro Ito

  第40回日本分子生物学会, 2017, Japanese, Domestic conference

  Poster presentation


• 乳癌発症が遺伝要因と環境要因に依存する可能性−乳癌モデルマウスの検討

  INOUE NANAKO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• 骨髄間質細胞が産生するオステオポンチンは造血幹・前駆細胞をCD44を介して支持する

  YANO MASAYA, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• The role of MED1 in breast carcinogenesis and progression

  MINEMATSU YUKI, INOUE NANAKO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第39回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• RAR-binding ability of MED1 is required for high-concentrationATRA-dependent activation of PML-RARα

  TAKAHARA TAKU, KAWAI ASAMI, MORI MAHIRO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第78回日本血液学会学術集会, 2016, Japanese, Domestic conference

  Poster presentation


• Periostin supports normal and malignant hematopoietic stem/progenitor cells in vitro.

  MAEKAWA AKIO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• Periostin supports hematopoietic stem/progenitor cells and niche-dependent myeloblastoma cells.

  TANAKA SATOWA, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• Periostin supports hematopoietic stem:progenitor cells and niche-dependent myeloblastoma cells in vitro

  MAEKAWA AKIO, HASEGAWA NATSUMI, ITO MITSUHIRO

  58th ASH Annual Meeting and Exposition, 2016, English, International conference

  Poster presentation


• Mediator subunit MED1 is required for PML-RARα fusion protein-induced transcriptional activation in response high concentration all-trans retinoic acid.

  TAKAHARA TAKU, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• MED1結合蛋白CCAR1とCoCoAはPPARγ2誘導性の白色脂肪細胞分化を司る

  TAKEMOTO YUSUKE, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• MED1-dependent and -independent coactivation mechanism of Mediator for GATA1 action

  MORI MAHIRO, KAWAI ASAMI, TAKAHARA TAKU, HASEGAWA NATSUMI, ITO MITSUHIRO

  第78回日本血液学会学術集会, 2016, Japanese, Domestic conference

  Poster presentation


• High-concentration ATRA-dependent activation of PML-RARα requires Mediator subunit MED1.

  KAWAI ASAMI, HASEGAWA NATSUMI, ITO MITSUHIRO

  日本血液学会, 2016, Japanese, Domestic conference

  Poster presentation


• GATA1による転写活性化におけるMED1依存性と非依存性の機序

  MORI MAHIRO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2016, Japanese, Domestic conference

  Poster presentation


• Periostin supports normal and malignant hematopoietic stem/progenitor cells in vitro.

  TANAKA SATOWA, HASEGAWA NATSUMI, ITO MITSUHIRO

  International Conference on The Tumour Microenvironment in the Haematological Malignancies and its Therapeutic Targeting, European, May 2015, English, International conference

  Poster presentation


• 乳癌発症が遺伝要因と環境要因に依存する可能性−乳癌モデルマウスの検討

  INOUE NANAKO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• 骨髄間質細胞が産生するオステオポンチンは造血幹・前駆細胞をCD44を介して支持する

  YANO MASAYA, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• Periostin supports normal and malignant hematopoietic stem:progenitor cells in vitro.

  MAEKAWA AKIO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• Periostin supports hematopoietic stem:progenitor cells and niche-dependent myeloblastoma cells.

  TANAKA SATOWA, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• Mediator subunit MED1 is required for PML-RARα fusion protein-induced transcriptional activation in response high concentration all-trans retinoic acid.

  TAKAHARA TAKU, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• MED1結合蛋白CCAR1とCoCoAはPPARγ2誘導性の白色脂肪細胞分化を司る

  TAKEMOTO YUSUKE, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• High-concentration ATRA-dependent activation of PML-RARα requires Mediator subunit MED1.

  KAWAI ASAMI, HASEGAWA NATSUMI, ITO MITSUHIRO

  第77回日本血液学会学術集会, 2015, Japanese, Domestic conference

  Poster presentation


• GATA1による転写活性化におけるMED1依存性と非依存性の機序

  MORI MAHIRO, HASEGAWA NATSUMI, ITO MITSUHIRO

  第38回日本分子生物学会, 2015, Japanese, Domestic conference

  Poster presentation


• FGF8 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro.

  RURI ISHINO, HASEGAWA NATSUMI, MITSUHIRO ITO

  Highlights of ASH in Asia, Mar. 2014, English, International conference

  [Invited]

  Invited oral presentation


• FGF7 supports hematopoietic stem and progenitor cells and niche-dependent myeloblastoma cells via autocrine action on bone marrow stromal cells in vitro.

  KEIJI MATSUI, HASEGAWA NATSUMI, MITSUHIRO ITO

  55th Annual Meeting of the American Society of Hematology, Dec. 2013, English, International conference

  Poster presentation


• PHYSICAL INTERACTION BETWEEN PPARγ AND MEDIATOR SUBUNIT MED1 IS CRUCIAL FOR INDUCED ADIPOCYTE HYPERTROPHY

  ITO MITSUHIRO, HASEGAWA NATSUMI

  MECHANISMS OF EUKARYOTIC TRANSCRIPTION 2013, Aug. 2013, English, Cold Spring Harbor Laboratory, International conference

  Poster presentation

• Japanese Society of Sonographers

• ホルモン依存性癌と転写コアクチベーターMED1：診断と治療標的の可能性

  長谷川 菜摘

  科学研究費補助金／若手研究, Apr. 2018 - Mar. 2022, Principal investigator

  Competitive research funding


• 基本的転写共役因子MED1が担う乳癌の発症と特性

  長谷川 菜摘

  学術研究助成基金助成金／若手研究(B), Apr. 2015 - Mar. 2018, Principal investigator

  Competitive research funding


• 転写メディエーターが担う乳癌の発癌と特性

  長谷川 菜摘

  科学研究費補助金／研究活動スタート支援, Aug. 2013 - Mar. 2015, Principal investigator

  Competitive research funding