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p53 and proliferating cell nuclear antigen expression in JC virus-infected cells of progressive multifocal
A Ariza1, J L Mate, A Fernández-Vasalo
1Department of Anatomic Pathology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Spain.
Abstract:
Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS) caused by infection with JC papova virus (JCV), is characterized by marked atypical changes in the glial cells. The JCV T protein binds cellular p53 (a tumor suppressor gene product), which as a result loses its normal down regulating influence on the cell cycle. We hypothesized that this binding would stabilize p53 and prolong its half life, leading to its immunohistochemical detection. To prove our theory combined JCV DNA:DNA in situ hybridization (ISH) and glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC) as well as p53/GFAP double IHC were performed on routinely processed sections of five brains obtained at autopsy and two cerebral biopsy specimens from seven patients with PML. All specimens showed JCV infected oligodendrocytes and bizarre looking astrocytes that immunostained strongly for p53. In addition, because loss of p53 function results in proliferating cell nuclear antigen (PCNA) overexpression PCNA/GFAP double IHC was carried out, and a positive immunoreaction was obtained in JCV infected cells in the two biopsy specimens. The evidence of p53 immunoreactivity in JCV harboring glial cells seems to indicate a link between the JCV induced stabilization/inactivation of p53 and the striking tumorlike glial changes seen in PML. Proliferating cell nuclear antigen overexpression in these cells further supports this pathogenetic construct.
Insights
Progressive multifocal leukoencephalopathy (PML) involves JC virus (JCV) infection, altering glial cells. Researchers found JCV T protein binding stabilizes p53, linking it to PML
Area of Science:
- Neurovirology
- Cellular Biology
- Pathology
Background:
- Progressive multifocal leukoencephalopathy (PML) is a CNS demyelinating disease caused by JC papova virus (JCV).
- PML is characterized by atypical glial cell changes.
- The JCV T protein interacts with the p53 tumor suppressor, potentially disrupting cell cycle regulation.
Purpose of the Study:
- To investigate the hypothesis that JCV T protein binding stabilizes p53, prolonging its half-life and enabling immunohistochemical detection.
- To explore the role of p53 stabilization in the pathogenesis of PML-associated glial changes.
Main Methods:
- Combined JCV DNA in situ hybridization (ISH) and glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC).
- p53/GFAP and PCNA/GFAP double IHC on autopsy and biopsy specimens from PML patients.
- Analysis of viral DNA, glial markers, p53, and proliferating cell nuclear antigen (PCNA) expression.
Main Results:
- All PML specimens showed JCV-infected oligodendrocytes and atypical astrocytes with strong p53 immunostaining.
- PCNA overexpression was observed in JCV-infected cells in biopsy specimens, indicating proliferation.
- Evidence suggests a link between JCV-induced p53 stabilization/inactivation and tumor-like glial changes in PML.
Conclusions:
- JCV infection leads to p53 stabilization and inactivation in glial cells.
- This p53 alteration is implicated in the characteristic tumor-like glial changes observed in PML.
- PCNA overexpression further supports the proposed pathogenetic mechanism involving p53 dysfunction.