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Logo of bmcgenoBioMed Centralsearchsubmit a manuscriptregisterthis articleBMC Genomics
 
BMC Genomics. 2009; 10: 201.
Published online Apr 28, 2009. doi:  10.1186/1471-2164-10-201
PMCID: PMC2683871
Activation of p53-regulated pro-apoptotic signaling pathways in PrP-mediated myopathy
Jingjing Liang,1 Debra Parchaliuk,2 Sarah Medina,2 Garrett Sorensen,2 Laura Landry,3 Shenghai Huang,1 Meiling Wang,1 Qingzhong Kong,corresponding author1 and Stephanie A Boothcorresponding author2,4
1Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
2Molecular PathoBiology, National Microbiology Laboratory, Winnipeg, Manitoba, R3E 3R2, Canada
3Prion Diseases Program, National Microbiology Laboratory, Winnipeg, Manitoba, R3E 3R2, Canada
4Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R3E 0W3, Canada
corresponding authorCorresponding author.
Jingjing Liang: jingjing.liang/at/case.edu; Debra Parchaliuk: Debra_Parchaliuk/at/phac-aspc.gc.ca; Sarah Medina: Sarah_Medina/at/phac-aspc.gc.ca; Garrett Sorensen: Garrett_Sorensen/at/phac-aspc.gc.ca; Laura Landry: Laura_Landry/at/phac-aspc.gc.ca; Shenghai Huang: huangs/at/ccf.org; Meiling Wang: Meiling.wang/at/case.edu; Qingzhong Kong: qxk2/at/case.edu; Stephanie A Booth: Stephanie_Booth/at/phac-aspc.gc.ca
Received March 25, 2009; Accepted April 28, 2009.
Abstract
Background
We have reported that doxycycline-induced over-expression of wild type prion protein (PrP) in skeletal muscles of Tg(HQK) mice is sufficient to cause a primary myopathy with no signs of peripheral neuropathy. The preferential accumulation of the truncated PrP C1 fragment was closely correlated with these myopathic changes. In this study we use gene expression profiling to explore the temporal program of molecular changes underlying the PrP-mediated myopathy.
Results
We used DNA microarrays, and confirmatory real-time PCR and Western blot analysis to demonstrate deregulation of a large number of genes in the course of the progressive myopathy in the skeletal muscles of doxycycline-treated Tg(HQK) mice. These include the down-regulation of genes coding for the myofibrillar proteins and transcription factor MEF2c, and up-regulation of genes for lysosomal proteins that is concomitant with increased lysosomal activity in the skeletal muscles. Significantly, there was prominent up-regulation of p53 and p53-regulated genes involved in cell cycle arrest and promotion of apoptosis that paralleled the initiation and progression of the muscle pathology.
Conclusion
The data provides the first in vivo evidence that directly links p53 to a wild type PrP-mediated disease. It is evident that several mechanistic features contribute to the myopathy observed in PrP over-expressing mice and that p53-related apoptotic pathways appear to play a major role.
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