Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis.
Neuronal degeneration associated with human immunodeficiency virus encephalitis has been attributed to neurotoxicity of signaling molecules secreted by activated, infected macrophages. We hypothesized that the barrage of signals present in the extracellular milieu of human immunodeficiency virus-infiltrated brain causes inappropriate activation of neuronal cell-cycle machinery. We examined the presence of three members of the cell-cycle control machinery: pRb, E2F1, and p53 in the simian immunodeficiency virus encephalitis (SIVE) model. Compared to noninfected and simian immunodeficiency virus-infected, nonencephalitic controls, we observed increased protein expression of E2F1 and p53 and aberrant cellular localization of E2F1 and pRb. In SIVE, E2F1 was abundant in the cytoplasm of neurons in both neurons and astrocytes proximal to SIVE pathology in the basal ganglia. pRb staining was nuclear and cytoplasmic in cortical neurons of SIVE cases. Antibodies to phosphorylated pRb also labeled the cytoplasm of cortical neurons. These data suggest that in SIVE, cell signaling results in phosphorylation of pRb which may result in subsequent alteration in E2F1 activity. As increased E2F1 and p53 activities have been linked to cell death, these data suggest that the neurodegeneration in SIVE could in part be because of changes in expression and activity of cell-cycle machinery.
Jordan-Sciutto
K L
KL
Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Wang
G
G
Murphy-Corb
M
M
Wiley
C A
CA
D000818:Animals; D001253:Astrocytes / Q000737:chemistry; D001479:Basal Ganglia / Q000737:chemistry; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000032:analysis*; D003593:Cytoplasm / Q000737:chemistry; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004660:Encephalitis / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005625:Frontal Lobe / Q000737:chemistry; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008954:Models, Biological; D009474:Neurons / Q000737:chemistry; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000032:analysis / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53