Activation of p53-regulated pro-apoptotic signaling pathways in PrP-mediated myopathy.
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.


CONCLUSIONS
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.
Liang
Jingjing
J
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. jingjing.liang@case.edu
Parchaliuk
Debra
D
Medina
Sarah
S
Sorensen
Garrett
G
Landry
Laura
L
Huang
Shenghai
S
Wang
Meiling
M
Kong
Qingzhong
Q
Booth
Stephanie A
SA
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018621:PrPC Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D018621:PrPC Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D004318:Doxycycline