Human Molecular Genetics Advance Access originally published online on July 31, 2009
Human Molecular Genetics 2009 18(21):4035-4045; doi:10.1093/hmg/ddp352
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p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR
1 University of Ottawa, Ottawa K1H 8M5, Canada, 2 Apoptosis Research Center, CHEO Research Institute, CHEO, Ottawa K1H 8L1, Canada 3 Johnson and Johnson Pharmaceutical Research & Development, San Diego, CA 92130, USA
* To whom correspondence should be addressed at: Children's Hospital of Eastern Ontario Research Institute, Apoptosis Research Center, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada. Tel: +1 6137372772; Fax: +1 6137384833; Email: mackenzie{at}cheo.on.ca/martin{at}arc.cheo.ca
Received May 26, 2009; Revised July 14, 2009; Accepted July 24, 2009
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of 
motor neurons resulting in progressive muscle atrophy. Reduced amount of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of SMN protein originating from the SMN2 gene compensating in part for the absence of functional SMN1 gene. Although there exists a sizeable literature on SMN2 inducing compounds, there is comparatively less known about the signaling pathways which modulate SMN levels. Here, we report a significant induction in SMN mRNA and protein following p38 activation by Anisomycin. We demonstrate that Anisomycin activation of p38 causes a rapid cytoplasmic accumulation of HuR, a RNA binding protein which binds to and stabilizes the AU-rich element within the SMN transcript. The stabilization of SMN mRNA, rather than transcriptional induction results in an increase in SMN protein. Our demonstration of SMN protein regulation through the p38 pathway and the role of HuR in this modulation may help in the identification and characterization of p38 pathway activators as potential therapeutic compounds for the treatment of SMA.