Kohei Miyazono

Summary

Affiliation: University of Tokyo
Country: Japan

Publications

  1. pmc Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Proc Jpn Acad Ser B Phys Biol Sci 85:314-23. 2009
  2. doi request reprint Tumour promoting functions of TGF-β in CML-initiating cells
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Tokyo 113 0033, Japan
    J Biochem 152:383-5. 2012
  3. pmc Tumor-promoting functions of transforming growth factor-β in progression of cancer
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo, Japan
    Ups J Med Sci 117:143-52. 2012
  4. ncbi request reprint Biology of transforming growth factor-β signaling
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Curr Pharm Biotechnol 12:2099-107. 2011
  5. doi request reprint Bone morphogenetic protein receptors and signal transduction
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Biochem 147:35-51. 2010
  6. doi request reprint Ectodomain shedding of HB-EGF: a potential target for cancer therapy
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biochem 151:1-3. 2012
  7. doi request reprint Arkadia--beyond the TGF-β pathway
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biochem 149:1-3. 2011
  8. pmc Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling
    Akiyoshi Komuro
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7 3 1, Bunkyo ku, Tokyo, Japan
    J Natl Cancer Inst 101:592-604. 2009
  9. ncbi request reprint Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1)
    Akiyoshi Komuro
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Oncogene 23:6914-23. 2004
  10. doi request reprint c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma
    Kunihiko Kiyono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Sci 100:1809-16. 2009

Detail Information

Publications99

  1. pmc Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Proc Jpn Acad Ser B Phys Biol Sci 85:314-23. 2009
    ..The discovery of molecules that inhibit TGF-beta-induced EMT but not TGF-beta-induced growth arrest may be an ideal strategy for treatment of invasion and metastasis of cancer...
  2. doi request reprint Tumour promoting functions of TGF-β in CML-initiating cells
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Tokyo 113 0033, Japan
    J Biochem 152:383-5. 2012
    ..TGF-β is known to maintain the CML-initiating cells through the Akt-FoxO pathway. Together, these findings suggest that TGF-β may exhibit multiple functions in progression of CML through acting on leukemia-initiating cells...
  3. pmc Tumor-promoting functions of transforming growth factor-β in progression of cancer
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo, Japan
    Ups J Med Sci 117:143-52. 2012
    ..These findings thus may be useful for establishing treatment strategies for advanced cancer by inhibiting TGF-β signaling...
  4. ncbi request reprint Biology of transforming growth factor-β signaling
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Curr Pharm Biotechnol 12:2099-107. 2011
    ..We also address major TGF-β-induced cell responses involved in several physiological and pathological conditions, including cell proliferation, fibrosis, and epithelial-mesenchymal transition...
  5. doi request reprint Bone morphogenetic protein receptors and signal transduction
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Biochem 147:35-51. 2010
    ..The recent development of BMP receptor inhibitors may also prove useful for some clinical diseases induced by hyperactivation of the BMP signalling pathways...
  6. doi request reprint Ectodomain shedding of HB-EGF: a potential target for cancer therapy
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biochem 151:1-3. 2012
    ..showed that CRM197 prevents the ectodomain shedding of proHB-EGF. Thus, these mAbs function as specific inhibitors for the ectodomain shedding of HB-EGF and may be useful for treating cancers exhibiting elevated levels of HB-EGF...
  7. doi request reprint Arkadia--beyond the TGF-β pathway
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biochem 149:1-3. 2011
    ..Arkadia interacts with the clathrin-adaptor 2 (AP2) complex and regulates endocytosis of certain cell surface receptors, leading to modulation of epidermal growth factor (EGF) and possibly other signalling pathways...
  8. pmc Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling
    Akiyoshi Komuro
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7 3 1, Bunkyo ku, Tokyo, Japan
    J Natl Cancer Inst 101:592-604. 2009
    ..However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail...
  9. ncbi request reprint Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1)
    Akiyoshi Komuro
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Oncogene 23:6914-23. 2004
    ..Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs...
  10. doi request reprint c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma
    Kunihiko Kiyono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Sci 100:1809-16. 2009
    ..These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis...
  11. doi request reprint Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature
    Mitsunobu R Kano
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo, 113 0033, Japan
    Cancer Sci 100:173-80. 2009
    ..In conclusion, the appropriate strategy for optimization of tumor vasculature for nanoparticles may differ depending on tumor type, and in particular on the degree of pericyte coverage around the vasculature...
  12. ncbi request reprint Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling
    Yoshiko Nagano
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biol Chem 282:20492-501. 2007
    ....
  13. doi request reprint BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo
    Yuka Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Cell Sci 123:1684-92. 2010
    ..These findings suggest that BMP-9 signaling activates the endothelium tested in the present study via ALK-1...
  14. pmc Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7
    Daizo Koinuma
    Department of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research JFCR, Toshima ku, Tokyo, Japan
    EMBO J 22:6458-70. 2003
    ..Arkadia may thus play an important role as an amplifier of TGF-beta superfamily signalling under both physiological and pathological conditions...
  15. doi request reprint Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma
    Erik Johansson
    Department of Molecular Pathology and the Global Center of Excellence Program for Integrative Life Science Based on the Study of Biosignaling Mechanisms, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Sci 101:2398-403. 2010
    ..These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2...
  16. doi request reprint SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells
    Mami Takahata
    Division of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research JFCR, Division of Molecular Pharmacology, the Cancer Chemotherapy Center of the JFCR, and Genome Center of the JFCR, Tokyo, Japan
    J Biol Chem 284:3334-44. 2009
    ..These findings reveal a novel mechanism where distinct transcriptional co-repressors are co-amplified and functionally interact, and provide molecular targets for gastric cancer treatment...
  17. ncbi request reprint Nuclear and cytoplasmic c-Ski differently modulate cellular functions
    Motoko Nagata
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Genes Cells 11:1267-80. 2006
    ..Mapping of the regions required for cytoplasmic accumulation by proteasome inhibitors suggests that subcellular localization of c-Ski may be regulated by proteasome-sensitive processes through amino acid residues 94-210 and 491-548...
  18. pmc Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski
    Masafumi Takeda
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan
    Mol Biol Cell 15:963-72. 2004
    ..We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-beta/activin signaling...
  19. doi request reprint Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles
    Yelena Vachutinsky
    Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8656, Japan
    J Control Release 149:51-7. 2011
    ..These results suggest that RGD targeted crosslinked polyplex micelles can be effective plasmid DNA carriers for antiangiogenic gene therapy...
  20. doi request reprint Identification of targets of Prox1 during in vitro vascular differentiation from embryonic stem cells: functional roles of HoxD8 in lymphangiogenesis
    Kaori Harada
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Cell Sci 122:3923-30. 2009
    ..These findings indicate that transcriptional networks of Prox1 and HoxD8 play important roles in the maturation and maintenance of lymphatic vessels...
  21. doi request reprint Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1
    Makoto Oba
    Department of Clinical Vascular Regeneration, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo, Tokyo 113 8655, Japan
    Mol Pharm 7:501-9. 2010
    ..Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application...
  22. pmc Smad7 inhibits transforming growth factor-beta family type i receptors through two distinct modes of interaction
    Yuto Kamiya
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biol Chem 285:30804-13. 2010
    ..Smad7 thus has an additional mode of interaction with TGF-β family type I receptors not possessed by Smad6, which may play roles in mediating the inhibitory effects unique to Smad7...
  23. doi request reprint Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells
    Yoshiko Nagano
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7 3 1, Bunkyo ku, Tokyo, Japan
    J Biochem 147:545-54. 2010
    ..Arkadia thus regulates the levels of expression of c-Ski protein in cell-type-dependent fashion, and exhibits a tumour suppressor function by inhibiting tumour cell growth...
  24. doi request reprint Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells
    Kunihiko Kiyono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Res 69:8844-52. 2009
    ..These findings show that TGF-beta signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-beta...
  25. pmc TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition
    Takuya Shirakihara
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    EMBO J 30:783-95. 2011
    ..Thus, TGF-β and FGF-2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression...
  26. ncbi request reprint Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling
    Yutaka Midorikawa
    Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4 6 1 Komaba, Meguro ku, Tokyo 153 8904, Japan
    Int J Cancer 103:455-65. 2003
    ..The modulation of growth factors by GPC3 may help explain its role in liver carcinogenesis. In addition, the ability of HCC cells to express GPC3 at high levels may serve as a new tumor marker for HCC...
  27. ncbi request reprint Transforming growth factor-beta promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1
    Shogo Ehata
    Department of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan
    Cancer Res 67:9694-703. 2007
    ..Our observations thus provide new insights into the molecular mechanisms governing TGF-beta-mediated cell survival and metastasis of cancer...
  28. pmc An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-beta signalling
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    EMBO J 27:2955-65. 2008
    ..HHM thus appears to regulate a subset of TGF-beta target genes including the Olig1-Smad synexpression group. HHM is the first example of a cellular response-selective regulator of TGF-beta signalling with clearly determined mechanisms...
  29. doi request reprint Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis
    Masako Oka
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Blood 111:4571-9. 2008
    ..These findings suggest that TGF-beta transduces signals in LECs and plays an important role in the regulation of lymphangiogenesis in vivo...
  30. ncbi request reprint c-Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases
    Norihiko Kobayashi
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Genes Cells 12:375-85. 2007
    ..We conclude that c-Ski induces myogenic differentiation through acting on MyoD and inhibiting HDAC activity in the nucleus of myogenic cells...
  31. ncbi request reprint Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling
    Yutaka Yoshida
    Department of Oncology, The Institute of Medical Science, University of Tokyo, 4 6 1 Shirokanedai, Minato ku, Tokyo 108, Japan
    Mech Dev 120:629-37. 2003
    ..Our results provide both in vitro and in vivo evidence that Tob inhibits endogenous BMP signaling by facilitating inhibitory Smad functions...
  32. pmc Cell type-specific target selection by combinatorial binding of Smad2/3 proteins and hepatocyte nuclear factor 4alpha in HepG2 cells
    Anna Mizutani
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    J Biol Chem 286:29848-60. 2011
    ....
  33. doi request reprint Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells
    Roy Akira Saito
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo, Japan
    Cancer Res 69:2783-91. 2009
    ....
  34. ncbi request reprint SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells
    Shigeo Matsuyama
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Cancer Res 63:7791-8. 2003
    ....
  35. doi request reprint Arkadia complexes with clathrin adaptor AP2 and regulates EGF signalling
    Anna Mizutani
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo, Japan
    J Biochem 148:733-41. 2010
    ..Arkadia thus appears to regulate EGF signalling by modulating endocytosis of EGFR through interaction with AP2 complex...
  36. ncbi request reprint TGF-beta signaling in embryonic stem cell-derived endothelial cells
    Tetsuro Watabe
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Japan
    Methods Mol Biol 330:341-51. 2006
    ..In this chapter, we present how to study the cellular and biochemical effects of TGF-beta signals on endothelial cells derived from mouse ESCs...
  37. ncbi request reprint c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements
    Hiroyuki Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Oncogene 23:5068-76. 2004
    ..These results suggest that stabilization of inactive Smad complexes on DNA is a critical event in c-Ski-mediated inhibition of TGF-beta signaling...
  38. pmc Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells
    Akira Watanabe
    Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan
    Proc Natl Acad Sci U S A 108:12384-9. 2011
    ..These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells...
  39. pmc TGF-beta receptor kinase inhibitor enhances growth and integrity of embryonic stem cell-derived endothelial cells
    Tetsuro Watabe
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo ku, Tokyo, Japan
    J Cell Biol 163:1303-11. 2003
    ..These results suggest that endogenous TGF-beta/activin signals play important roles in regulating vascular growth and permeability...
  40. pmc Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension
    Ayako Nishihara
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan
    Mol Biol Cell 13:3055-63. 2002
    ..The differences in biological activities among the BMPR-II mutants observed thus suggest that additional genetic and/or environmental factors may play critical roles in the pathogenesis of PPH...
  41. doi request reprint miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma
    Hironori Matsuyama
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan
    Blood 118:6881-92. 2011
    ..These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment...
  42. doi request reprint Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1
    Yasuhiro Yoshimatsu
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Cell Sci 124:2753-62. 2011
    ..Furthermore, we found that both Prox1 and Ets-2 bind to the VEGFR3 promoter in intact chromatin. These findings suggest that Ets family members function as transcriptional cofactors that enhance Prox1-induced lymphangiogenesis...
  43. doi request reprint Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-beta inhibitor
    Michiaki Kumagai
    Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8656, Japan
    J Control Release 140:306-11. 2009
    ..Use of the PEG-PAsp-coated magnetite nanoparticles, combined with the TGF-beta inhibitor, is of promising clinical importance for the detection of intractable solid cancers, including pancreatic cancer...
  44. doi request reprint VEGFR2-PLCgamma1 axis is essential for endothelial specification of VEGFR2+ vascular progenitor cells
    Hitoshi Sase
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan
    J Cell Sci 122:3303-11. 2009
    ..Taken together, these findings indicate that VEGFR2-PLCgamma1 signal relay gives rise to the unique function of VEGFR2, thus enabling endothelial differentiation from vascular progenitors...
  45. pmc Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling
    Mitsunobu R Kano
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033 Japan
    Proc Natl Acad Sci U S A 104:3460-5. 2007
    ..The use of TbetaR-I inhibitor combined with nanocarriers may thus be of significant clinical and practical importance in treating intractable solid cancers...
  46. doi request reprint Polyplex micelles from triblock copolymers composed of tandemly aligned segments with biocompatible, endosomal escaping, and DNA-condensing functions for systemic gene delivery to pancreatic tumor tissue
    Kanjiro Miyata
    Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
    Pharm Res 25:2924-36. 2008
    ....
  47. ncbi request reprint Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells
    Konosuke Nakayama
    Division of Endocrinology, Department of Medicine, University of Tokyo School of Medicine, Tokyo, Japan
    J Bone Miner Res 18:827-35. 2003
    ..Because direct phosphorylation of Smad1 by ERKs is not required for the inhibition, other transcriptional factors that are phosphorylated by ERKs might be involved in the regulation of osteoblastic differentiation by ERKs...
  48. ncbi request reprint Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line
    Shogo Ehata
    Department of Biochemistry, the Cancer Institute of the Japanese Foundation for Cancer Research JFCR, Koto ku, Tokyo, Japan
    Cancer Sci 98:127-33. 2007
    ..These findings suggest that TbetaR-I kinase inhibitors such as Ki26894 may be useful for blocking the progression of advanced cancers...
  49. pmc Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells
    Kyoko Kawasaki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113 0033, Japan
    J Cell Biol 181:131-41. 2008
    ..VEGF-A thus activates temporally distinct Ras-Erk signaling to direct endothelial specification of VEGFR2(+) vascular progenitor cells...
  50. doi request reprint Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells
    Takashi Kokudo
    Department of Molecular Pathology, Graduate School of Medicine and the Global Center of Excellence Program for Integrative Life Science Based on the Study of Biosignaling Mechanisms, The University of Tokyo, Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Cell Sci 121:3317-24. 2008
    ..These results indicate that Snail mediates the actions of endogenous TGFbeta signals that induce EndMT...
  51. pmc Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression
    Yasuhiro Yoshimatsu
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo ku, Tokyo 113 0033, Japan
    Proc Natl Acad Sci U S A 110:18940-5. 2013
    ..Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation. ..
  52. doi request reprint Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-β
    Yoko Katsuno
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Pathol 228:391-404. 2012
    ..Targeting REG4 in ALDH1+ CICs may provide a novel strategy in the treatment of diffuse-type gastric carcinoma...
  53. pmc Widespread inference of weighted microRNA-mediated gene regulation in cancer transcriptome analysis
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Tokyo 113 0033, Japan
    Nucleic Acids Res 41:e62. 2013
    ..This approach proposes a next-generation strategy for the interpretation of miRNA function and identification of target miRNAs as biomarkers and therapeutic targets...
  54. doi request reprint p53 actions on microRNA expression and maturation pathway
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Methods Mol Biol 962:165-81. 2013
    ..In this chapter, we describe the methods for evaluation of the effects of p53 on miRNA expression, an interaction between pri-miRNA and Drosha complex, and pri-miRNA processing activity of the Drosha complex...
  55. pmc Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals
    Hikaru Nishimori
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biol Chem 287:20037-46. 2012
    ....
  56. ncbi request reprint BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells
    Hideyo Miyazaki
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Oncogene 23:9326-35. 2004
    ..Furthermore, this is the first report of a role for BMP signaling in reducing growth kinetics of androgen-insensitive prostate tumors...
  57. ncbi request reprint Smad4-independent regulation of p21/WAF1 by transforming growth factor-beta
    Hideaki Ijichi
    Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8655, Japan
    Oncogene 23:1043-51. 2004
    ..The upregulation occurs through Smad2/3-dependent transcriptional activation of the p21/WAF1 promoter region. These results suggest a novel mechanism of gene regulation, that is, a novel signal mediator other than Smad4...
  58. pmc Glioma-initiating cells retain their tumorigenicity through integration of the Sox axis and Oct4 protein
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Biol Chem 286:41434-41. 2011
    ..Our findings reveal differences between glioma-initiating cells and fetal neural progenitor cells and may open the way to depriving glioma-initiating cells of tumorigenic activity without affecting normal tissues...
  59. doi request reprint Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene
    Shourong Wu
    Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
    Mol Ther 16:1227-34. 2008
    ..In the light of these findings, PHD2 silencing by RNAi might offer a potential tool for angiogenic therapy...
  60. doi request reprint Development of stabilin2+ endothelial cells from mouse embryonic stem cells by inhibition of TGFbeta/activin signaling
    Hidenori Nonaka
    Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1 1 1 Yayoi, Bunkyo ku, Tokyo 113 0032, Japan Japan Health Sciences Foundation, Chuo Ku, Tokyo, Japan
    Biochem Biophys Res Commun 375:256-60. 2008
    ..Our results reveal that TGFbeta/activin signaling negatively regulates the early events of HSEC differentiation...
  61. pmc Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGF-beta
    Takuya Shirakihara
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Mol Biol Cell 18:3533-44. 2007
    ....
  62. doi request reprint Role of Ras signaling in the induction of snail by transforming growth factor-beta
    Kana Horiguchi
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Tokyo 113 0033, Japan
    J Biol Chem 284:245-53. 2009
    ....
  63. pmc ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif
    Masato Morikawa
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo, Japan
    Nucleic Acids Res 39:8712-27. 2011
    ..These results provide insights into the molecular mechanism of BMP signaling and the pathogenesis of vascular lesions of certain genetic disorders, including hereditary hemorrhagic telangiectasia...
  64. doi request reprint Engineering fibrotic tissue in pancreatic cancer: a novel three-dimensional model to investigate nanoparticle delivery
    Hitomi Hosoya
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Biochem Biophys Res Commun 419:32-7. 2012
    ..Thus our novel technique provides a promising in vitro means to investigate permeation of nanoparticles in fibrotic tissue, when both type and number of fibroblasts can be regulated...
  65. pmc Bone morphogenetic protein-2 and -4 play tumor suppressive roles in human diffuse-type gastric carcinoma
    Yo taro Shirai
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Am J Pathol 179:2920-30. 2011
    ..Our findings suggest that BMP-2 and BMP-4 function as potent tumor suppressors in diffuse-type gastric carcinoma...
  66. doi request reprint MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Mol Cell 44:424-36. 2011
    ..The presence of this abortive processing machinery and diversity of MCPIP1-related genes may imply a dynamic evolutional transition of the RNA silencing system...
  67. ncbi request reprint Tenth Japanese-German Workshop on Molecular and Cellular Aspects of Carcinogenesis, Essen, Germany, 29 September-1 October 2005
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan corrected
    Cancer Sci 97:332-9. 2006
  68. ncbi request reprint Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors
    Kouichiro Goto
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biol Chem 282:20603-11. 2007
    ..Although Smad6 regulates BMP signaling through multiple mechanisms, our findings suggest that interaction with type I receptors is a critical step in the function of Smad6...
  69. ncbi request reprint Roles of vascular endothelial growth factor receptor 3 signaling in differentiation of mouse embryonic stem cell-derived vascular progenitor cells into endothelial cells
    Hiroyuki Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Blood 105:2372-9. 2005
    ..Thus, VEGFR2 signaling is required for the endothelial differentiation of mouse ES cells induced by VEGF-C, and VEGFR3 signaling may confer lymphatic endothelial-like phenotypes to ECs...
  70. ncbi request reprint Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis
    Caname Iwata
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Res 67:10181-9. 2007
    ..Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis...
  71. ncbi request reprint BMPs promote proliferation and migration of endothelial cells via stimulation of VEGF-A/VEGFR2 and angiopoietin-1/Tie2 signalling
    Yuka Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo, Japan
    J Biochem 143:199-206. 2008
    ..BMP-4 also increased the expression and phosphorylation of VEGFR2 and Tie2. These findings suggest that BMP signalling activates endothelium via activation of VEGF/VEGFR2 and Angiopoietin/Tie2 signalling...
  72. doi request reprint Regulation of the stability of cell surface E-cadherin by the proteasome
    Masao Saitoh
    Department of Molecular Pathology, University of Tokyo, Bunkyo ku, Japan
    Biochem Biophys Res Commun 381:560-5. 2009
    ..However, promotion of cell migration by TGF-beta was not significantly affected by proteasome inhibition. Proteasome-dependent events thus appear to be involved in stabilization of cell surface E-cadherin...
  73. doi request reprint Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors
    Hiroaki Ikushima
    Department of Molecular Pathology, University of Tokyo, Japan
    Cell Stem Cell 5:504-14. 2009
    ..These results identify an essential pathway for GICs, the TGF-beta-Sox4-Sox2 pathway, whose disruption would be a therapeutic strategy against gliomas...
  74. doi request reprint A crucial role of a high mobility group protein HMGA2 in cardiogenesis
    Koshiro Monzen
    Department of Cardiovascular Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 8655, Japan
    Nat Cell Biol 10:567-74. 2008
    ..5 gene, both in P19CL6 cells and in transgenic Xenopus embryos. Thus, HMGA2 is a positive regulator of Nkx2.5 gene expression and is essential for normal cardiac development...
  75. doi request reprint COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction
    Tomoko Yamazaki
    Department of Molecular Pathology, Graduate School of Medicine, Global Center of Excellence Program for Integrative Life Science Based on the Study of Biosignaling Mechanisms, University of Tokyo, Bunkyo ku, Tokyo 113 0033, Japan
    Genes Cells 14:425-34. 2009
    ..These results suggest that COUP-TFII physically and functionally interact during differentiation and maintenance of lymphatic vessels...
  76. doi request reprint Identification of a phosphorylation site in c-Ski as serine 515
    Motoko Nagata
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan
    J Biochem 148:423-7. 2010
    ..Identification of the phosphorylation site of c-Ski would allow us further examination of physiological significance of c-Ski phosphorylation...
  77. ncbi request reprint Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo
    Emi Tokuda
    Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
    Cancer Res 67:9666-76. 2007
    ..These results indicate that CKIP-1, a novel Akt PH domain-interacting protein, would be a candidate of tumor suppressor with an Akt inhibitory function...
  78. ncbi request reprint VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling
    Mitsunobu R Kano
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo 113 0033, Japan
    J Cell Sci 118:3759-68. 2005
    ..The findings provide insights into the mechanisms underlying the effects of co-stimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies...
  79. ncbi request reprint Coordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteins
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Oncogene 23:4232-7. 2004
    ....
  80. doi request reprint Promoter-wide analysis of Smad4 binding sites in human epithelial cells
    Daizo Koinuma
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo ku, Tokyo
    Cancer Sci 100:2133-42. 2009
    ..Our findings revealed some general characteristics of Smad4 binding regions, and provide resources for examining the role of Smad4 in epithelial cells and cancer pathogenesis...
  81. ncbi request reprint BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Cytokine Growth Factor Rev 16:251-63. 2005
    ..Moreover, recent findings have revealed that BMP pathways interact with other signaling pathways, and such signaling cross-talk plays pivotal roles in growth and differentiation of target cells...
  82. ncbi request reprint Functional domains of Runx1 are differentially required for CD4 repression, TCRbeta expression, and CD4/8 double-negative to CD4/8 double-positive transition in thymocyte development
    Masahito Kawazu
    Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    J Immunol 174:3526-33. 2005
    ..These results suggest that the activation domain is essential for Runx1 to establish thymocyte development and that Runx1 has both TLE-dependent and TLE-independent functions in thymocyte development...
  83. doi request reprint Specificity of the inhibitory effects of Dad on TGF-beta family type I receptors, Thickveins, Saxophone, and Baboon in Drosophila
    Yuto Kamiya
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1, Hongo, Bunkyo ku, Tokyo, Japan
    FEBS Lett 582:2496-500. 2008
    ..Dad inhibited Saxophone (ALK-1/2 orthologue) and Thickveins (ALK-3/6 orthologue) but not Baboon (ALK-4/5/7 orthologue). The differential modes of action of I-Smads in mammals and Drosophila are discussed...
  84. pmc Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades
    Koichi Mishima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Mol Biol Cell 18:1421-9. 2007
    ....
  85. ncbi request reprint A new partner for inhibitory Smads
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, 113 0033, Tokyo, Japan
    Cytokine Growth Factor Rev 13:7-9. 2002
  86. ncbi request reprint Two major Smad pathways in TGF-beta superfamily signalling
    Keiji Miyazawa
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Japan
    Genes Cells 7:1191-204. 2002
    ..Understanding the mechanisms of TGF-beta superfamily signalling is thus important for the development of new ways to treat various clinical diseases in which TGF-beta superfamily signalling is involved...
  87. ncbi request reprint Regulation of transforming growth factor-beta signaling and vascular diseases
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Cancer Institute of the Japanese Foundation for Cancer Research, Japan
    Cornea 21:S48-53. 2002
    ..Therefore, understanding these signaling mechanisms may provide us with novel ways to develop strategies for treating clinical diseases induced by these cytokines...
  88. doi request reprint TGFbeta signalling: a complex web in cancer progression
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    Nat Rev Cancer 10:415-24. 2010
    ....
  89. ncbi request reprint Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation
    Miyuki Suzawa
    Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan
    J Bone Miner Res 17:240-8. 2002
    ....
  90. ncbi request reprint Regulation of TGF-beta signaling and its roles in progression of tumors
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan
    Cancer Sci 94:230-4. 2003
    ..Abnormalities of these regulators of TGF-beta signaling may thus participate in the progression of various tumors...
  91. ncbi request reprint Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells
    Tatsuru Ota
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    J Cell Physiol 193:299-318. 2002
    ..These results revealed some new targets of TGF-beta in endothelial cells, and differences in transcriptional regulation patterns between ALK-1 and ALK-5...
  92. ncbi request reprint Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane
    Chie Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    J Biol Chem 277:39919-25. 2002
    ..Thus, these results suggest that the plasma membrane localization of Smad7 by Smurf1 requires the C2 domain of Smurf1 and is essential for the inhibitory effect of Smad7 in the transforming growth factor-beta signaling pathway...
  93. doi request reprint Roles of TGF-beta family signaling in stem cell renewal and differentiation
    Tetsuro Watabe
    Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Cell Res 19:103-15. 2009
    ..Here, we illustrate the roles of TGF-beta family members in the maintenance and differentiation of ES cells, somatic stem cells, and cancer stem cells...
  94. pmc Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo
    Yuichi Ikeda
    Division of Hematopoietic Factors and Department of Advanced Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan
    Proc Natl Acad Sci U S A 101:10732-7. 2004
    ..Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders...
  95. doi request reprint Cellular context-dependent "colors" of transforming growth factor-beta signaling
    Hiroaki Ikushima
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Cancer Sci 101:306-12. 2010
    ..Such methods will aid specific regulation of either the tumor-suppressive or tumor-promoting arm of the TGF-beta pathway and in realization of TGF-beta-based treatment of malignant tumors...
  96. ncbi request reprint Ninth Japanese-German Workshop on Molecular and Cellular Aspects of Carcinogenesis, Essen, Germany, 18-20 September, 2003
    Kohei Miyazono
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Cancer Sci 95:276-81. 2004
    ..Additional support from many other sponsors in Germany and Japan is gratefully acknowledged. The Workshop participants are listed at the end of this Report...
  97. doi request reprint Modulation of microRNA processing by p53
    Hiroshi I Suzuki
    Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Nature 460:529-33. 2009
    ..Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology...
  98. ncbi request reprint Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro
    Kimiko Yamamoto
    Dept of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo 113 0033, Japan
    Am J Physiol Heart Circ Physiol 288:H1915-24. 2005
    ....
  99. ncbi request reprint IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism
    Kazuyuki Nakagome
    Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7 3 1 Hongo, Bunkyo ku, Tokyo, Japan
    J Immunol 179:284-94. 2007
    ..Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response...