We previously reported that Moloney murine leukemia virus-ts1-mediated neuronal degeneration in mice is likely a result of both loss of glial support and release of cytokines and neurotoxins from ts1-infected glial cells. Viral infection in some cell types regulates expression of p53 protein, a key regulator of cell proliferation and death. Therefore, we hypothesized that p53 and its dependent genes may be linked with ts1-mediated neuropathology. We examined the presence of p53 and its dependent gene product, a proapoptotic protein bax-α, in ts1-induced spongiform encephalomyelopathy. Compared with controls, the lesions of infected animals contained increased levels of p53 and bax-α in astrocytes, as shown by strong nuclear p53 and cytoplasmic bax-α immunoreactivity in astrocytes. To determine how ts1 affects p53 expression in astrocytes, we then assessed the expression of p53 and its dependent genes, such as bax-α and p21, in infected and uninfected immortalized C1 astrocytes and studied possible pathways responsible for p53 accumulation in infected astrocytes. In these studies using mitogen-activated protein kinase inhibitors, infection-induced increases in the p53 level were partially blocked by PD98059, a synthetic inhibitor of MEK1 that is the immediate upstream kinase of extracellular signal-regulated kinases 1/2 (ERK1/2), but not by SB202190, a potent p38 kinase inhibitor. Furthermore, treatment with PD98059 significantly decreased the level of p21 protein, a p53-dependent gene product. These results suggest that ts1 infection may stabilize p53 protein through activation of ERKs in C1 astrocytes, leading to increased expression of the p21 and bax-α proteins, both of which induce cell cycle arrest and apoptosis. Our studies suggest that ts1 neuropathology in mice may result from changes in expression and activity of p53, brought about in part by ts1 activation of ERK.
|Original language||English (US)|
|Number of pages||10|
|State||Published - Jun 2002|
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology