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

Liang J, Parchaliuk D, Medina S, Sorensen G, Landry L, Huang S, Wang M, Kong Q, Booth SA - BMC Genomics (2009)

Bottom Line: 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.The data provides the first in vivo evidence that directly links p53 to a wild type PrP-mediated disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. jingjing.liang@case.edu

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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Mechanism of PrP-mediated myopathy. Accumulation of an N-terminal truncated PrP C1 fragment in muscle activates p53 resulting in the induction of p53-regulated pro-apoptotic networks and myopathic changes. PrPC over-expression also results in down-regulation of MEF2C, which may be partially responsible for the progressive central nuclei localization observed in the muscles of Dox-treated Tg(HQK) mice.
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Figure 7: Mechanism of PrP-mediated myopathy. Accumulation of an N-terminal truncated PrP C1 fragment in muscle activates p53 resulting in the induction of p53-regulated pro-apoptotic networks and myopathic changes. PrPC over-expression also results in down-regulation of MEF2C, which may be partially responsible for the progressive central nuclei localization observed in the muscles of Dox-treated Tg(HQK) mice.

Mentions: We propose a working model to explain the mechanism of PrP-mediated myopathy (Figure 7). Dox-induced over-expression of PrPC in the muscles leads to accumulation of the N-terminal truncated PrP C1 fragment, which in turn activates p53, thereby inducing p53-regulated pro-apoptotic networks and myopathic changes.


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

Liang J, Parchaliuk D, Medina S, Sorensen G, Landry L, Huang S, Wang M, Kong Q, Booth SA - BMC Genomics (2009)

Mechanism of PrP-mediated myopathy. Accumulation of an N-terminal truncated PrP C1 fragment in muscle activates p53 resulting in the induction of p53-regulated pro-apoptotic networks and myopathic changes. PrPC over-expression also results in down-regulation of MEF2C, which may be partially responsible for the progressive central nuclei localization observed in the muscles of Dox-treated Tg(HQK) mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683871&req=5

Figure 7: Mechanism of PrP-mediated myopathy. Accumulation of an N-terminal truncated PrP C1 fragment in muscle activates p53 resulting in the induction of p53-regulated pro-apoptotic networks and myopathic changes. PrPC over-expression also results in down-regulation of MEF2C, which may be partially responsible for the progressive central nuclei localization observed in the muscles of Dox-treated Tg(HQK) mice.
Mentions: We propose a working model to explain the mechanism of PrP-mediated myopathy (Figure 7). Dox-induced over-expression of PrPC in the muscles leads to accumulation of the N-terminal truncated PrP C1 fragment, which in turn activates p53, thereby inducing p53-regulated pro-apoptotic networks and myopathic changes.

Bottom Line: 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.The data provides the first in vivo evidence that directly links p53 to a wild type PrP-mediated disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. jingjing.liang@case.edu

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.

Show MeSH
Related in: MedlinePlus