Induction of p53 accumulation by Moloney murine leukemia virus-ts1 infection in astrocytes via activation of extracellular signal-regulated kinases 1/2.
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-alpha, in ts1-induced spongiform encephalomyelopathy. Compared with controls, the lesions of infected animals contained increased levels of p53 and bax-alpha in astrocytes, as shown by strong nuclear p53 and cytoplasmic bax-alpha 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-alpha 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-alpha 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.
Kim
Hun-Taek
HT
Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas.
Tasca
Serban
S
Qiang
Wenan
W
Wong
Paul K Y
PK
Stoica
George
G
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000821:virology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology / Q000821:virology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D018792:Encephalitis, Viral / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005419:Flavonoids / Q000627:therapeutic use; D007942:Leukemia, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D008979:Moloney murine leukemia virus / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one