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Function of the interacting protein of SMN, the product of the spinal muscular atrophy gene, and neural specific splicing.

Research Project

Project/Area Number 10670619
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionNational Institute of Neuroscience, NCNP

Principal Investigator

TSUKAHARA Toshifumi  National Institute of Neuroscience, NCNP, Senior Staff Researcher, 神経研究所, 研究員 (60207339)

Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordssppinal muscular atrophy (SMA) / amyotrophic lateral scleosis (ALS) / SMN / RNA splicing / SR proteins / NSSR 1 and 2 / SIP1(-α) / SIP1-β / SMA / 筋萎縮性側索硬化症 / ALS / SIP1 / スプライシング因子 / スペックル / P19細胞 / GluR2遺伝子
Research Abstract

SMN protein, the product of the SMA gene, is considered to play a crucial role in biogenesis of spliceosomes with the SMN-interacting protein, SIP1. To clarify splicing mechanism in neuron, we searched neural splicing factors and cloned two new SR proteins, Neural-salient SR proteins (NSSR) 1 and 2, which are present at higher levels in brain and testis. During the differentiation, NSSR 1 is detected only in the neuronal stage. Both the purified recombinant NSSR 1 and 2 proteins enhance the in vitro splicing activity of nuclear extract. Moreover, overexpression of NSSR 2 prevents the inclusion of either the Flip or Flop exons in the splicing of the GluR-B gene, resulting in an increase in the abnormal exon-skipping product. In contrast, transient transfection with NSSR 1 promotes the inclusion of the Flip exon so that the abnormal product is spliced to the mature spliced form. This suppression of exon skipping by NSSR 1 is observed even with cotransfection of NSSR 2. Results indicate that NSSR 1 may play a crucial role in the regulation of alternative splicing in neurons.
Next, to clarify relevancy of pathogenesis and SIP1, we identified three novel splicing variants of the SIP1 (SIP-β、γ and δ), in addition to the full-length SIP1-α (280AA). We examined the expression levels of these splicing variants in various normal human tissues and in muscle samples from patients with SMA and ALS. The SIP1-α was a major product and ubiquitiously expressed. In contrast, SIP-β and γ were detected at very low expression level. In patients with SMA and ALS, the SIP-α was dramatically decreased(17%, 19%) compared to the controls, while the SIP-β was significantly increased(34%, 32%) in both diseases. These findings suggest that aberrant alternative splicing event in SIP1 occur in the motor neuron disease and contribute the pathological process of SMA and ALS.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Masaaki Komatsu et al.: "Cloning and characterization of two neural-salient serine/arginine-rich(NSSR)proteins involved in the regulation of altemative splicing in neurons"Genes to Cells. 4. 593-606 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ayako Shinozaki et al.: "Changes in expressions of splicing factors during the neuronal differentiation of P19 embryonal carcinoma cells"Int. J Biochem. Cell Biol. 31. 1279-1287 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hirotaka Koizumi et al.: "Apoptosis in favourable neuroblastomas is not dependent on Fas(CD95/APO-1)expression but on activated caspase 3(CPP32)"J. Pathol.. 189. 410-415 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yukiko K. Hayashi et al.: "Mutations in the integrin α7 gene cause congenital myopathy"Nature Genetics. 19. 94-97 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Eriko Fujita et al.: "Wortmannin enhances activation of CPP32(Caspase-3)induced by TNF or anti-Fas"Cell Death and Differentiation. 5. 287-297 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shinichiro Kubo et al.: "Presence of emerinopathy in cases of regid spine syndrome"Neuromusc Disord. 8. 502-507 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yukiko K. Hayashi, Fan-Li Chou, Eva Engvall, Megumu Ogawa, Chie Matsuda, Shinichi Hirabayashi, Kenji Yokochi, Barry L. Ziober, Randall H. Kramer, Stephan J. Kaufman, Eijiro Ozawa, Yu-ichi Goto, Ikuya Nonaka, Toshifumi Tsukahara, Jian-zhou Wang, Eric P. Hoffman and Kiichi Arahata: "Mutations in the integrin α7 gene cause congenital myopathy."Nature Genetics. 19. 94-97 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Eriko Fujita, Yoriko Kouroku, Yasuko Miho, Toshifumi Tsukahara, Shoichi Ishiura and Takashi Momoi: "Wortmannin enhances activation of CPP32(Caspase-3) induced by TNF or anti-Fas."Cell Death and Differentiation. 5. 287-297 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yoriko Kouroku, Akiko Soyama, Eriko Fujita, Koko Urase, Toshifumi Tsukahara and Takashi Momoi: "RA70 is a Src kinase-associated protein expressed ubiquitously."Biochem Biophys Res Commun.. 252. 738-742 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shinichiro Kubo, Toshifumi Tsukahara, Masakazu Takemitsu, Kim BonYoon, Hiroya Utsumi, Ikuya Nonaka and Kiichi Arahata: "Presence of emerinopathy in cases of rigid spine syndrome."Neuromusc Disord.. 8. 502-507 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hirotaka Koizumi, Ikuo Ohkawa, Toshifumi Tsukahara, Takashi Momoi, Koonosuke Nakada and Toshiyuki Uchikoshi: "Apoptosis in favourable neuroblastomas is not dependent on Fas(CD95/APO-1) expression but on activated caspase 3 (CPP32)."J. Pathol.. 189. 410-415 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ayako Shinozaki, Kiichi Arahata and Toshifumi Tsukahara: "Changes in expressions of splicing factors during the neuronal differentiation of P19 embryonal carcinoma cells."Int. J. Biochem. Cell biol.. 31. 1279-1287 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masaaki Komatsu, Eiki Kominami, Kiichi Arahata and Toshifumi Tsukahara: "Cloning and characterization of two neural-salient serine/argininerich (NSSR) proteins involved in the regulation of alternative splicing in neurons."Genes to Cells. 4. 593-606 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Masaaki Komatsu: "Cloning and characterization of two neural-salient serine/arginine-rich (NSSR) proteins involved in the regulation of alternative splicing in neurons"Genes to Cells. 4. 593-606 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ayako Shinozaki: "Changes in expressions of splicing factors during the neuronal differentiation of P19 embryonal carcinoma cells"Int. J. Biochem. Cell Biol.. 31. 1279-1287 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hirotaka Koizumi: "Apoptosis in favourable neuroblastomas is not dependent on Fas (CD95/APO-1) expression but on activated caspase 3 (CPP32)"J. Pathol.. 189. 410-415 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yukiko K.Hayashi 他: "Mutations in the integrin 7 gene cause congenital myopathy." Nature Genetics. 19. 94-97 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Eriko Fujita 他: "Wortmannin enhances activation of CPP32(Caspase-3)induced by TNF or anti-Fas." Cell Death and Differentiation. 5. 287-297 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoriko Kouroku 他: "RA70 is a Src kinase-associated protein expressed ubiquitously." Biochem Biophys Res Commun.252. 738-742 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shinichiro Kubo 他: "Presence of emerinopathy in cases of rigid spine syndrome." Neuromusc Disord.8. 502-507 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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