Abnormal differentiation of tumor cells and tyrosine kinase regulation

• Project/Area Number: 17014069
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University (2008-2009); Kyushu University (2005-2007)
• Principal Investigator: YOSHIMURA Akihiko Keio University, 医学部, 教授 (90182815)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥59,900,000 (Direct Cost: ¥59,900,000); Fiscal Year 2009: ¥12,900,000 (Direct Cost: ¥12,900,000); Fiscal Year 2008: ¥12,900,000 (Direct Cost: ¥12,900,000); Fiscal Year 2007: ¥11,400,000 (Direct Cost: ¥11,400,000); Fiscal Year 2006: ¥11,400,000 (Direct Cost: ¥11,400,000); Fiscal Year 2005: ¥11,300,000 (Direct Cost: ¥11,300,000)
• Keywords: サイトカイン / シグナル伝達 / チロシンキナーゼ / 転写因子 / STAT / 炎症 / Ras / ERK / 家族性変異 / 発がん / Spred / 神経繊維腫I型 / SOCS / Sred / 肝炎 / 肝がん / チロシンりん酸化 / インターフェロン

Research Abstract

Inflammatory cells are involved in tumor growth and development through various inflammatory mediators. Inflammatory cytokines activate the NF-kB and JAK/STAT pathways. We have investigated the function of SOCS family and Spred family proteins which regulate cytokine signaling, on tumorigenesi. In model mice lacking SOCS1 or SOCS3 genes, we found that carcinogen-induced tumorigensis was promoted. In human hepatocellular carcinoma, SOCS1 and SOCS3 gene expression was silenced. We also found that human SPRED1 is responsible for neurofibromatosis type I like disease.

Research Products

• [Journal Article] Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. (2009)
  • Author(s): Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, Iwaki T, Okada Y, Iida M, Cua DJ, Iwakura Y, Yoshimura A
  • Journal Title: Nature Med. 15(8) Pages: 946-950
• [Journal Article] SOCS3 in T and NKT cells negatively regulates cytokine production and ameliorates ConA-induced hepatitis. (2009)
  • Author(s): Nakaya M, Hashimoto M, Nakagawa R, Wakabayashi Y, Ishizaki T, Takada I, Komai K, Yoshida H, Yoshimura A
  • Journal Title: J Immunol 183(11) Pages: 7047-7053
• [Journal Article] Clinical and mutational spectrum of Legius syndrome (2009)
  • Author(s): Messiaen L, Yao S, (他30名), Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E
  • Journal Title: JAMA 302(19) Pages: 2111-2118
• [Journal Article] Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. (2009)
  • Author(s): Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O, Esposito B, Perez N, Yasukawa H, Van Snick J, Yoshimura A, Tedgui A, Mallat Z
  • Journal Title: J Exp Med. 206(10) Pages: 2067-2077
• [Journal Article] Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis. (2009)
  • Author(s): Taniguchi K, Sasaki K, Watari K, Yasukawa H, Imaizumi T, Ayada T, Okamoto F, Ishizaki T, Kato R, Kohno R, Kimura H, Sato Y, Ono M, Yonemitsu Y, Yoshimura A
  • Journal Title: PLoS ONE 4(5)
• [Journal Article] Cyclic adenosine monophosphate suppresses the transcription of proinflammatory cytokines via the c-Fos protein phosphorylated by IKKbeta (2009)
  • Author(s): Koga K, Takaesu G, Yoshida R, Nakaya M, Kobayashi T, Kinjyo I, Yoshimura A
  • Journal Title: Immunity 30(3) Pages: 372-383
• [Journal Article] Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation (2009)
  • Author(s): Hashimoto M, Ayada T, Kinjyo I, Hiwatashi K, Yoshida H, Okada Y Kobayashi T, Yoshimura A
  • Journal Title: Cancer Sci 100(4) Pages: 730-736
  • NAID: 10025144745
• [Journal Article] Rudensky AY. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. (2009)
  • Author(s): Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K
  • Journal Title: Immunity 30(1) Pages: 80-91
• [Journal Article] Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4, 5-biphosphate hydrolysis. (2009)
  • Author(s): Ayada T, Taniguchi K, Okamoto F, Kato R, Komune S, Takaesu G, Yoshimura A
  • Journal Title: Oncogene 28(8) Pages: 1076-88
• [Journal Article] Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein (2009)
  • Author(s): Keiko Koga, et al.
  • Journal Title: Immunity 30 Pages: 372-383
  • Peer Reviewed
• [Journal Article] Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1{alpha}-Induced Chemotaxis in T Cells. (2009)
  • Author(s): Sekine Y, Ikeda O, Tsuji S, et al.
  • Journal Title: J Immunol. 183(12) Pages: 7966-7974
  • Peer Reviewed
• [Journal Article] Clinical and mutational spectrum of Legius syndrome (2009)
  • Author(s): Messiaen L, Yao S, Brems H, et al.
  • Journal Title: JAMA 206(10) Pages: 2067-2077
  • Peer Reviewed
• [Journal Article] Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. (2009)
  • Author(s): Shichita T, Sugiyama Y, Ooboshi H., et al.
  • Journal Title: Nature Med. 15(8) Pages: 946-950
  • Peer Reviewed
• [Journal Article] Sprouty4 negatively regulates protein kinase C activation by inhibiting phoshatidylinositol 4,5-biphosphate hydrolysis. (2009)
  • Author(s): Ayata T, Taniguchi K, et al.
  • Journal Title: Oncogene 28 Pages: 1076-1088
  • Peer Reviewed
• [Journal Article] Sprouty4 deficiency potentiates Ras-independent angiogenic signals and tumor growth. (2009)
  • Author(s): Taniguchi K, Ishizaki T, Ayada T, et al.
  • Journal Title: Cancer Sci. 100(9) Pages: 1648-1654
  • Peer Reviewed
• [Journal Article] Cyclic Adenosine Monophosphate Suppresses the Transcription of Prninflammatnry Cvtokines via the Phosnhorvlated c-Fos Protein (2009)
  • Author(s): Keiko Koga, et.al.
  • Journal Title: Immunity 30 Pages: 372-383
  • Peer Reviewed
• [Journal Article] Sprouty4 negatively regulates protein kinase C activation by inhibiting phosnhatidvlinositol 4.5-biphosphate hydrolysis (2009)
  • Author(s): Ayata T, Taniguchi K, et.al.
  • Journal Title: Oncogene 28 Pages: 1076-1088
  • Peer Reviewed
• [Journal Article] STAT6 inhibits TGF-beta 1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. (2008)
  • Author(s): Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T
  • Journal Title: J Biol Chem. 283(22) Pages: 14955-14962
• [Journal Article] TRAF6 and MEKK1 Play a Pivotal Role in the RIG-I-like Helicase Antiviral Pathway. (2008)
  • Author(s): Yoshida R, Takaesu G, Yoshida H, Okamoto F, Yoshioka T, Choi Y, Akira S, Kawai T, Yoshimura A, Kobayashi T
  • Journal Title: J Biol Chem. 283(52) Pages: 36211-36220
• [Journal Article] FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicases signaling pathway. (2008)
  • Author(s): Sanada T, Takaesu G, Mashima R, Yoshida R, Kobayashi T, Yoshimura A
  • Journal Title: J Biol Chem. 283(49) Pages: 33858-33864
• [Journal Article] Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis. (2008)
  • Author(s): Torisu T, Nakaya M, Watanabe S, Hashimoto M, Yoshida H, Chinen T, Yoshida R, Okamoto F, Hanada T, Torisu K, Takaesu G, Kobayashi T, Yasukawa H, Yoshimura A
  • Journal Title: Hepatology 47(5) Pages: 1644-1654
• [Journal Article] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads. (2008)
  • Author(s): Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A
  • Journal Title: J Immunol 180(6) Pages: 3746-3756
• [Journal Article] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag. (2008)
  • Author(s): Ryo A, Tsurutani N, Ohba K, Kimura R, Komano J, Nishi M, Soeda H, Hattori S, Perrem K, Yamamoto M, Chiba J, Mimaya J, Yoshimura K, Matsushita S, Honda M, Yoshimura A, Sawasaki T, Aoki I, Morikawa Y, Yamamoto N
  • Journal Title: Proc Natl Acad Sci U S A 105(1) Pages: 294-299
• [Journal Article] FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicases signaling pathway (2008)
  • Author(s): Sanada T, Takaesu G, Yoshida R, Kobayashi T, et.al.
  • Journal Title: Journal of Biological Chemistry 283 Pages: 33858-33864
  • Peer Reviewed
• [Journal Article] Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat (2008)
  • Author(s): Ichiyama K, Chinen, T, Kobayashi T, et.al.
  • Journal Title: J Biological Chemistry 283 Pages: 10773-10778
  • Peer Reviewed
• [Journal Article] SOCS1 protects mice against concanavalin-A-induced hepatitis by inhibiting Fas, STAT1 and JNK-mediated apoptosis (2008)
  • Author(s): Torisu T, Chinen T, Yasukawa H. Kobayashi T, et.al.
  • Journal Title: Hepatology 47 Pages: 1644-1654
  • Peer Reviewed
• [Journal Article] FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging (2008)
  • Author(s): Miyamoto K, Miyamoto T, Kato R
  • Journal Title: Blood 112 Pages: 4485-4493
  • Peer Reviewed
• [Journal Article] Loss of Suppressor of Cytokine Signaling 1 in Helper T Cells Leads to Defective Th17 Differentiation by Enhancing Antagonistic Effects of IFN-{gamma} on STAT3 and Smads. (2008)
  • Author(s): Tanaka, K・Kobayashi, T・Yoshimura, A, et. al.
  • Journal Title: J Immunol. 180 Pages: 3746-56
  • Peer Reviewed
• [Journal Article] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellualt trafficking and stability of HIV-1 Gag. (2008)
  • Author(s): Ryo, A・Yoshimura, A・Aoki, I・Morikawa, Y・Yamamoto, N., et. al.
  • Journal Title: Porc Natl Acad Sci USA. 105 Pages: 294-9
  • Peer Reviewed
• [Journal Article] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • Author(s): Yoshimura A, Naka T, Kubo M
  • Journal Title: Nat Rev Immunol 7(6) Pages: 454-465
• [Journal Article] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (2007)
  • Author(s): Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E
  • Journal Title: Nature Genet 39(9) Pages: 1120-1126
• [Journal Article] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. (2007)
  • Author(s): Taniguchi K, Kohno R, Ayada T, Kato R, Ichiyama K, Morisada T, Oike Y, Yonemitsu Y, Maehara Y, Yoshimura A
  • Journal Title: Mol Cell Biol. 27(12) Pages: 4541-4550
• [Journal Article] Germline loss-of-function mutations in SPRED1 cause a neuofibromatosis 1-like phenotype. (2007)
  • Author(s): Brems, H・Marynen, P・Thomas, G・Yoshimura, A・Legius, E, et. al.
  • Journal Title: Nature Genet. 39 Pages: 1120-6
  • Peer Reviewed
• [Journal Article] Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokin signaling 3-deficient dendritic cells. (2007)
  • Author(s): Matsumura, Y・Wyss-Coray, T・Sato, K・Yoshimura, A, et. al.
  • Journal Title: J Immunol. 179 Pages: 2170-9
  • Peer Reviewed
• [Journal Article] SOCS3 Protein Developmentally Regulates the Chemokine Receptor CXCR4-FAK Signaling Pathway during B Lymphopoiesis. (2007)
  • Author(s): Le, Y・Yoshimura, A・Silberstein, LE, et. al.
  • Journal Title: Immunity. 27 Pages: 811-823
  • Peer Reviewed
• [Journal Article] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • Author(s): Yoshimura, A・Naka, T・Kubo, M
  • Journal Title: Nat Rev Immunol. 7 Pages: 454-65
  • Peer Reviewed
• [Journal Article] Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. (2007)
  • Author(s): Taniguchi, K・Maehara, Y・Yoshimura, A., et. al.
  • Journal Title: Mol Cell Biol 27 Pages: 4541-50
  • Peer Reviewed
• [Journal Article] Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling. (2007)
  • Author(s): Taniguchi K, Ayada T, Ichiyama K, Yoshimura A, et al.
  • Journal Title: Biochem Biophys Res Commun. 352(4) Pages: 896-902
• [Journal Article] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. (2006)
  • Author(s): Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A
  • Journal Title: J Exp Med. 203(6) Pages: 1391-1397
• [Journal Article] Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. (2006)
  • Author(s): Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y, Koga K, Takaesu G, Maehara Y, Iida M, Yoshimura A
  • Journal Title: Gastroenterology 131(1) Pages: 179-193
• [Journal Article] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. (2006)
  • Author(s): Yoshida T, Hisamoto T, Akiba J, Koga H, Nakamura K, Tokunaga Y, Hanada S, Kumemura H, Maeyama M, Harada M, Ogata H, Yano H, Kojiro M, Ueno T, Yoshimura A, Sata M
  • Journal Title: Oncogene 25(45) Pages: 6056-6066
• [Journal Article] Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. (2006)
  • Author(s): Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H
  • Journal Title: Nature Med. 12(7) Pages: 829-834
• [Journal Article] Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1. (2006)
  • Author(s): Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A
  • Journal Title: J Exp Med. 203(4) Pages: 1021-1031
• [Journal Article] Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. (2006)
  • Author(s): Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, Iida M, Kobayashi T, Yoshimura A
  • Journal Title: Oncogene 25(17) Pages: 2520-2530
• [Journal Article] Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. (2006)
  • Author(s): Lu Y, Fukuyama S, Yoshida R, Yoshimura A, Takaesu G, et al.
  • Journal Title: J Biol Chem. 281(48) Pages: 36683-36690
• [Journal Article] TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. (2006)
  • Author(s): Takaki H, Minoda Y, Yoshimura A, Kobayashi T, et al.
  • Journal Title: Genes Cells. 11(8) Pages: 871-882
• [Journal Article] Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. (2006)
  • Author(s): Ogata H, Kobayashi T, Chinen T, Takaki H, Yoshimura A, et al.
  • Journal Title: Gastroenterology. 131(1) Pages: 179-193
• [Journal Article] IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. (2006)
  • Author(s): Hanada T, Kobayashi T, Chinen T, Saeki K, Yoshimura A, et al.
  • Journal Title: J Exp Med. 203(6) Pages: 1391-1397
• [Journal Article] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. (2006)
  • Author(s): Yoshida T, Hisamoto T, Akiba J, Yoshimura A, Sata M, et al.
  • Journal Title: Oncogene. 25(45) Pages: 6056-6066
• [Journal Article] Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-betal production. (2006)
  • Author(s): Ogata H, Chinen T, Yoshida T, Yoshimura A, et al.
  • Journal Title: Oncogene. (in press)
• [Journal Article] Suppressor of Cytokine Signaling-1 Regulates Inflammatory Bowel Disease in Which Both IFNgamma and IL-4 Are Involved. (2006)
  • Author(s): Chinen T, Kobayashi T, Ogata H, Yoshimura A, et al.
  • Journal Title: Gastroenterology. 130(2) Pages: 373-388
• [Journal Article] Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice. (2006)
  • Author(s): Inagaki-Ohara K, Sasaki A, Matsuzaki G, Yoshimura A, et al.
  • Journal Title: Gut. 55(2) Pages: 212-219
• [Journal Article] The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1. (2005)
  • Author(s): Nonami A, Taketomi T, Kimura A, Yoshimura A, et al.
  • Journal Title: Genes Cells. 10(9) Pages: 887-895
• [Journal Article] Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. (2005)
  • Author(s): Taketomi T, Yoshiga D, Taniguchi K, Yoshimura A, et al.
  • Journal Title: Nat Neurosci. 8(7) Pages: 855-857
• [Journal Article] Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene. (2005)
  • Author(s): Hanada T, Tanaka K, Yoshimura A, et al.
  • Journal Title: J Immunol. 174(7) Pages: 4325-4332
• [Presentation] SOCS is a molecular link between inflammation and cancer development. International symposium of infection-associated cancers (2010)
  • Author(s): Akihiko Yoshimura
  • Organizer: Conference Hall of Hokkaido University in Sapporo
  • Place of Presentation: Hokkaido, Japan
• [Presentation] Role of SOCS1 in innate and adaptive immune tolerance (2010)
  • Author(s): Akihiko Yoshimura
  • Organizer: World Immune Regulation Meeting IV
  • Place of Presentation: Davos Switzerland
• [Presentation] sponsored by Aegean ConferencesAldeamar Knossos Royal Village in Hersonissos (2009)
  • Author(s): Akihiko Yoshimura
  • Organizer: Molecular basis for immune suppression by TGFb/Smad2/3 5th Leukocyte Signal Transduction Workshop
  • Place of Presentation: Crete, Greece
• [Presentation] SOCS1 and SOCS3 are Critical Regulators of Cytokine Signaling; Implication for Helper T Cell Differentiation and Tumor Development. (2007)
  • Author(s): Akihiko Yoshimura
  • Organizer: Implication for Helper T Cell Differentiation and Tumor Development
  • Place of Presentation: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Keystone USA
• [Presentation] SOCS1 is a link between inflammation and inflammation-mediated carcinogenesis. (2007)
  • Author(s): Akihiko Yoshimura
  • Organizer: 5th International Aachen Symposium on Cytokine Signalling
  • Place of Presentation: Aachen Germany
• [Remarks]
  • URL: http://www.new.immunoreg.jp/
• [Remarks]
  • URL: http://www.immunoreg.jp/