Study of therapeutic targets that cause functional defects in blood cells from myelodysplastic syndrome patients

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591400
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Fukushima Medical University
• Principal Investigator: SHIKAMA Yayoi 福島県立医科大学, 医学部, 准教授 (40291562)
• Co-Investigator(Kenkyū-buntansha): SHICHISHIMA Tsutomu 福島県立医科大学, 医学部, 博士研究員 (10192105) ; NOJI Hideyoshi 福島県立医科大学, 医学部, 講師 (20347214)
• Project Period (FY): 2011 – 2013
• Keywords: 骨髄異形成症候群 / FOS / 好中球 / RNA安定生 / 翻訳停止

Research Abstract

FOS is an immediate early gene whose expression level is rapidly increased under translation arrest in the cells exposed to DNA-damaging stresses. We found that translation arrest-induced elevation of FOS mRNA was attenuated in neutrophils from myelodysplastic syndrome (MDS) patients. The aberrant FOS mRNA induction was not due to reduced transcriptional activity but insufficient mRNA stabilization. In some patients, the expression levels of HuR, an mRNA-binding protein that stabilizes FOS mRNA, was decreased compared to those in healthy controls. Further, two microRNAs targeting FOS mRNA were increased in two-third of the patients tested. Our study indicated that the aberrant expressions of HuR and microRNAs resulted in the attenuated FOS mRNA induction in MDS.

Research Products

• [Journal Article] A new method for maturity-dependent fractionation of neutrophil progenitors applicable for the study of myelodysplastic syndromes (2014)
  • Author(s): Hu H, Shikama Y, Shichishima T, Ikeda K, Akutsu K, Ono T, Kimura H, Ogawa K, Noji H, Takeishi Y, Kimura J
  • Journal Title: Biomark Res Volume: 2 Pages: 2
• [Journal Article] 好中球の遺伝子発現調節異常から探る病態～骨髄異形成症候群～ (2014)
  • Author(s): 色摩(亀岡)弥生
  • Journal Title: 福島医学会誌 Volume: 64 Pages: 1-10
• [Journal Article] Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplastic syndrome patients (2013)
  • Author(s): Feng X, Shikama Y, Shichishima T, Noji H, Ikeda K, Ogawa K, Kimura H, Takeishi Y, Kimura J
  • Journal Title: PLoS One Volume: 8(4) Pages: e61107
• [Journal Article] Pharmacokinetic and pharmacodynamic interaction of nadolol with itraconazole, rifampicin and grapefruit juice in healthy volunteers (2013)
  • Author(s): Misaka S, Miyazaki N, Yatabe MS, Ono T, Shikama Y, Fukushima T, Kimura J
  • Journal Title: J Clin Pharmacol Volume: 53 Pages: 738-745
• [Journal Article] Effect of oral L-arginine administration on exhaled nitric oxide (NO) concentration in healthy volunteers (2013)
  • Author(s): Ogata H, Yatabe M, Misaka S, Shikama Y, Sato S, Munakata M, Kimura J
  • Journal Title: Fukushima J Med Sci Volume: 59 Pages: 43-48
• [Journal Article] Maturity-dependent fractionation of neutrophil progenitors : a new method to examine in vivo expression profiles of differentiation-regulating genes (2012)
  • Author(s): Hu H, Shikama Y, Shichishima T, Ikeda K, Akutsu K, Ono T, Kimura H, Ogawa K, Noji H, Takeishi Y, Kimura J
  • Journal Title: Exp Hematol Volume: 40 Pages: 675-681
• [Journal Article] 分化制御因子のin vivo expression profile解析のための好中球前駆細胞の分化段階別分画採取法 (2012)
  • Author(s): 色摩弥生
  • Journal Title: 日本薬理学会誌 Volume: 141 Pages: 90-94
• [Journal Article] Impairment of FOS mRNA induction by a translation inhibitor puromycin in granulocytes from myelodysplastic syndrome patients (2011)
  • Author(s): Shikama Y, Feng X, Shichishima T, Ono T, Noji H, Ikeda K, Ogawa K, Takeishi Y, Kimura J
  • Journal Title: Br J Haematol Volume: 154(4) Pages: 525-527
• [Presentation] Involvement of microRNAs and an RNA-binding protein in impaired stabilization of FOS mRNA under translation arrest in myelodysplastic syndrome-derived neutrophils (2014)
  • Author(s): Shikama Y, Cao M, Anzai M, Feng X, Noji H, Kimura H, Ogawa K, Ikeda K, Takeishi Y, Kimura J
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台市
  • Year and Date: 20140300
• [Presentation] (2013)
  • Author(s): Shikama Y, Cao M, Feng X, Kimura H, Noji H, Ogawa K, Ikeda K, Shichishima T, Takeishi Y, Kimura J
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2013-10-12
• [Presentation] 骨髄異形成症候群患者好中球におけるFOS mRNA安定化不全へのmiRNAの関与 (2013)
  • Author(s): 色摩弥生、曹美婉、馮暁敏、安斎美智子、野地秀義、小川一英、木村秀夫、竹石恭知、木村純子
  • Organizer: 第64回日本薬理学会北部会
  • Place of Presentation: 旭川市
  • Year and Date: 2013-09-13
• [Presentation] Impairment of HuR-mediated FOS mRNA stabilization via AU-rich element-binding protein HuR in granulocytes from myelodysplastic syndrome patients (2012)
  • Author(s): Feng X, Shikama Y, Noji H, Shichishima T, Ikeda K, Ogawa K, Kimura H, Takeishi Y, Kimura J
  • Organizer: 福島医学会第436回学術研究集会
  • Place of Presentation: 福島市
  • Year and Date: 2012-10-26
• [Presentation] Mechanisms of impaired FOS mRNA induction by emetine in granulocytes from myelodysplastic syndrome petinets (2012)
  • Author(s): Feng X, Shikama Y, Shichishima T, Noji H, Ikeda K, Ogawa K, Kimura H, Takeishi Y, Kimura J
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2012-10-21
• [Presentation] Impairment of emetne-induced FOS mRNA stabilization in granulocytes from myelodysplastic syndrome patients (2012)
  • Author(s): Feng X, Shikama Y, Noji H, Shichishima T, Ikeda K, Ogawa K, Takeishi Y, Kimura
  • Organizer: 第63回日本薬理学会北部会
  • Place of Presentation: 新潟市
  • Year and Date: 2012-09-14
• [Presentation] FOS induction by emetine via p38 MAPK and RNA-binding protein HuR in human granulocytes (2012)
  • Author(s): Feng X, Shikama Y, Kimura J
  • Organizer: 第85回日本薬理学会年会
  • Place of Presentation: 京都市
  • Year and Date: 2012-03-14
• [Presentation] p38 MAPK-mediated transcription and HuR-associated mRNA stabilization in FOS induction by emetine in human granulocytes (2011)
  • Author(s): Feng X, Shikama Y, Kimura J
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2011-12-16
• [Presentation] Mechanisms of immediate early gene FOS induction by emetine in human granulocytes (2011)
  • Author(s): Feng X, Shikama Y, Kimura J
  • Organizer: 第62回日本薬理学会北部会
  • Place of Presentation: 仙台市
  • Year and Date: 2011-09-29
• [Presentation] Impairment of FOS mRNA stabilization following translation arrest in granulocytes from myelodysplasrtic syndromes (2011)
  • Author(s): Feng X, Shikama Y, Noji H, Shichishima T, Ikeda K, Ogawa K, Kimura H, Shichishima T, Yakeishi Y, Kimura J
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡市
  • Year and Date: 2011-03-23
• [Presentation] Impairment of HuR-mediated FOS mRNA stabilization in granulocytes from myelodysplastic syndrome patients (2010)
  • Author(s): Feng X, Shikama Y, Shichishima T, Noji H, Ikeda K, Ogawa K, Takeishi Y, Kimura
  • Organizer: The 55^<th> American Spciety of Hematology Annual Meeting
  • Place of Presentation: Atlanta, GA, USA
  • Year and Date: 2010-12-09