Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis - PubMed (original) (raw)

Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis

K L Jordan-Sciutto et al. Am J Pathol. 2000 Aug.

Abstract

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.

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Figures

Figure 1.

Figure 1.

SIV-infected macaques with encephalitis show increased immunostaining for E2F1 and pRb. A: Macaques infected with SIV but without SIVE showed little to no staining for E2F1 in the basal ganglia. B: Macaques with SIVE showed robust staining for E2F1 in both nuclei and cytoplasm of basal ganglia cells. C: E2F1 staining was particularly intense in the cytoplasm of cells surrounding multinucleated giant cells. D: In the basal ganglia of macaques with SIVE Rb staining was restricted to select nuclei. Eand F: In the cortex of macaques with SIVE Rb staining was observed in both cytoplasm and nuclei of cells with neuronal morphology particularly in regions with microglial nodules (arrows). Scale bar, 20 μm.

Figure 2.

Figure 2.

In the frontal cortex of macaques with SIVE nuclei of astrocytes and neurons immunostain for Rb as does the cytoplasm of some neurons. Frontal cortex from macaque with SIVE immunostained for pRb (red) and MAP2 (green) (top) and GFAP (green) in (bottom) visualized by double-label immunofluorescent laser confocal microscopy. Single label for the cell type marker (red), pRb (green), and an overlay of the two images. Yellow-orange shows co-localization. Increased Rb staining was predominantly localized to nuclei of neurons and astrocytes, however, some MAP2-positive neurons also show cytoplasmic staining (arrows). Scale bar, 20 μm.

Figure 3.

Figure 3.

Neurons of the basal ganglia and frontal cortex of macaques with SIVE show cytoplasmic staining for E2F1, E2F1 (Cy3, red), and MAP2 (FITC, green) labeling in the basal ganglia (top) and frontal cortex (bottom) of a macaque with SIVE. Each marker is shown separately and as an overlay of the two images to show co-localization (yellow-orange). Scale bar, 20 μm.

Figure 4.

Figure 4.

In SIVE, cytoplasmic staining of E2F1 occurs in astrocytes of the basal ganglia but not the frontal cortex. Double-label immunofluorescent confocal microscopy for E2F1 (Cy3, red) and GFAP (FITC, green) are shown for the basal ganglia (top) and the frontal cortex (bottom) of a SIVE case. Single labels are shown in the appropriate color followed by double-label on right. Co-localization will appear yellow-orange. In SIVE E2F1 staining extends into the cytoplasm of astrocytes in the basal ganglia, however in the frontal cortex staining is predominantly restricted to nuclei. Scale bar, 20 μm.

Figure 5.

Figure 5.

The pRb observed in the neuronal cytoplasm of SIVE cases is phosphorylated. SIV-infected macaques exhibit little staining for a phospho-isoform of pRb in the frontal cortex (SIV-CTX). In SIV-infected monkeys with encephalitis phosphorylated pRb is present in the cytoplasm of numerous cells in the frontal cortex (SIVE-CTX).

Figure 6.

Figure 6.

Expression of E2F1 and p53 is increased in basal ganglia of SIVE cases. The amount of E2F1 and p53 present in control (lanes 1–3), SIV (lanes 4 and 5), and SIVE (lanes 6–8) cases was determined by immunoblot. Two hundred μg of protein were loaded into each lane of a 10% SDS-PAGE. The gel was immunoblotted for E2F1, p53, and actin as a control. Expression of these proteins was assessed in protein extracts from both the basal ganglia (top) and the frontal cortex (bottom).

Figure 7.

Figure 7.

Model of the proposed role for cell-cycle regulators in the SIVE progression. In normal neurons, E2F1 and pRb are found in the nucleus in complex with DP1 bound to promoter elements of S-phase-specific genes maintaining low expression of these genes (left). At this time TRAF2 is bound to the death receptor (DR) such as p75NTFR and initiates a survival signal (left). In response to extracellular signals released by infiltrating macrophages, pRb becomes phosphorylated and accumulates in the cytoplasm (right). E2F1 expression increases and accumulates in the cytoplasm where it causes degradation of TRAF2 (right). Degradation of TRAF2 allows the death receptor (DR) to interact with death domain containing proteins. Stimulation of the death receptor by neurotrophic factors (NTF) will lead to activation of the death domain proteins leading to cell death.

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