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Human Molecular Genetics Advance Access published online on January 12, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl482
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© The Author 2007. Published by Oxford University Press. All rights reserved

Stat5 constitutive activation rescues defects in spinal muscular atrophy

Chen-Hung Ting1,3, Chiao-Wei Lin2,3, Shin-Lan Wen1,3, Hsiu-Mei Hsieh-Li4 and Hung Li1,3,*

1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan 2 Faculty Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan 3 Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan 4 Department of Life Science, National Taiwan Normal University, Taipei 106, Taiwan

* Corresponding author: Hung Li, Ph.D. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Fax: +886-2-2782-6085, Phone: +886-2-27880460, E-mail: hungli{at}ccvax.sinica.edu.tw

Received October 3, 2006; Revised December 28, 2006; Accepted December 28, 2006

Proximal spinal muscular atrophy (SMA) is a motor neuron degeneration disorder for which there is currently no effective treatment. Here, we report three compounds (sodium vanadate, Trichostatin A, and aclarubicin) that effectively enhance SMN2 expression by inducing Stat5 activation in SMA-like mouse embryonic fibroblasts and human SMN2 transfected NSC34 cells. We found that Stat5 activation enhanced SMN2 promoter activity with increase of both full-length and deletion exon7 SMN transcripts in SMN2-NSC34 cells. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. In addition, constitutive activation of Stat5 mutant (Stat5A1*6) profoundly increased the number of nuclear gems in SMA-patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects. These results demonstrate that Stat5 signaling could be a possible pharmacological target for treating SMA.


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