Studies with GFP-Vpr fusion proteins: induction of apoptosis but ablation of cell-cycle arrest despite nuclear membrane or nuclear localization

Waldhuber, Megan G; Bateson, Michael; Tan, Judith; Greenway, Alison L.; McPhee, Dale A.

doi:10.1016/s0042-6822(03)00258-7

Cited by 39 publications

(47 citation statements)

References 61 publications

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“…Also, in agreement with others, we noted that high levels of Vpr could be toxic to cells and could result in the appearance of a NF-B, AP-1, and HIV LTR-repressed cell phenotype, especially at concentrations higher than 1 ng/ml (31,75). This repressed cell phenotype was observed mostly with Vpr-(52-96), in agreement with the reported proapoptotic activity of the C terminus of Vpr (35,45).…”

Section: Discussionsupporting

confidence: 90%

Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-κB and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages

Varin

Decrion

Sabbah

et al. 2005

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 90%

Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-κB and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages

Varin

Decrion

Sabbah

et al. 2005

Journal of Biological Chemistry

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“…4,45 On the other hand, mutants of Vpr have been described, which are able to dissociate both phenotypes partially. [46][47][48][49] The results from the present study suggest yet a different model. We propose that G 2 arrest and apoptosis are induced concomitantly, since both are dependent on activation of the same kinase, ATR.…”

Section: Discussioncontrasting

confidence: 47%

ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis

et al. 2005

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The human immunodeficiency virus type-1 (HIV-1) accessory gene vpr encodes a conserved 96-amino-acid protein that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. Expression of vpr in CD4 þ lymphocytes results in G 2 arrest, followed by apoptosis. In a previous study, we identified the ataxia telangiectasia-mutated (ATM) and Rad3-related protein (ATR) as a cellular factor that mediates Vpr-induced cell cycle arrest. In the present study, we report that the breast cancer-associated protein-1 (BRCA1), a known target of ATR, is activated in the presence of Vpr. In addition, the gene encoding the growth arrest and DNA damage-45 protein a (GADD45a), a known transcriptional target of BRCA1, is upregulated by Vpr in an ATRdependent manner. We demonstrate that RNAi-mediated silencing of either ATR or GADD45a leads to nearly complete suppression of the proapoptotic effect of Vpr. Our results support a model in which Vpr-induced apoptosis is mediated via ATR phosphorylation of BRCA1, and consequent upregulation of GADD45a.

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“…38 Unlike previous reports linking Vpr to G 2 /M arrest and apoptosis, 39,40 our research did not show a link between this cell cycle arrest and an enhanced rate of apoptosis in infected cells. 40 Those previous reports relied heavily on transfecting Vpr alone whereas our study was based on whole virus infection. As we reported, infection may lead to IL-2 up-regulation, which has been linked to the conferring of protection of infected cells against apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

Bahbouhi

Landay

Al‐Harthi

2004

Blood

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Using intracellular p24 staining to discriminate between bystander and HIV productively infected cells, we evaluated the properties of HIV productively infected cells in terms of cytokine expression, activation status, apoptosis, and cell proliferation. We demonstrate that HIV productively infected primary CD4 ؉ T cells express 12-to 47-fold higher type 1 cytokines than bystander or mock-infected cells. The frequency of HIV productive replication occurred predominantly in Thelper 1 (Th1), followed by Th0, then by Th2 cells. These productively infected cells expressed elevated levels of CD95, CD25, CXC chemokine receptor 4 (CXCR4), and CC chemokine receptor 5 (CCR5). While productively infected cells were only 1.8-fold higher in apoptosis frequency, they up-regulated the antiapoptotic protein B-cell leukemia 2 (Bcl-2) by 10-fold. Up-regulation of interleukin-2 (IL-2) and Bcl-2 were dependent on phosphatidylinositol-3-kinase signal transduction, given that it was down-regulated by Wortmanin treatment. Additionally, 60% of productively infected cells entered the cell cycle, as evaluated by Ki67 staining, but none divided, as evaluated by carboxyfluoresccin diacetate succinimidyl ester (CFSE) staining. Evaluation of cell cycle progression by costaining for DNA and RNA indicated that the cells were arrested in G 2 /M. Collectively, these data indicate that HIV replication occurs predominantly in Th1 cells and is associated with immune activation and up-regulation of Bcl-2, conferring a considerable degree of protection against apoptosis in the productively infected subpopulation. IntroductionThe interaction between cytokines and HIV expression is multifaceted. Approaches to evaluate the relationship between cytokines and HIV have relied on (1) evaluating the impact of a particular cytokine on HIV replication in vitro, [1][2][3][4][5] (2) comparing the cytokine expression profile of HIV-infected and uninfected donors, 6,7 and (3) measuring cytokine production from in vitro infected cells. [8][9][10] Analysis of the impact of cytokines on HIV-1 replication in vitro have generally demonstrated that a number of type 1 cytokines (interleukin-1 [IL-1], tumor necrosis factor-␣ [TNF-␣], IL-2, IL-12) up-regulate HIV replication while type 2 cytokines down-modulate HIV (IL-10, transforming growth factor-␤ [TGF-␤]). This relationship is not simplistic given that a combination of type 1 and type 2 cytokines may lead to a synergistic or antagonistic effects on HIV replication [11][12][13][14] ; this result often depends on the combination of cytokines and on the cell type examined, whether lymphocytic or monocytic.Earlier studies describing the cytokine profile in purified peripheral blood mononuclear cells (PBMCs) from HIV ϩ patients have led to discordant findings. Some suggested that HIV-1 infection leads to a shift from type 1 (IL-2, interferon-␥ [IFN-␥]) to type 2 (IL-4, IL-10) cytokines with HIV disease progression. 6 By contrast, others have not been able to document such a type 1-to-type 2 cytokine shift with disease pro...

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Studies with GFP-Vpr fusion proteins: induction of apoptosis but ablation of cell-cycle arrest despite nuclear membrane or nuclear localization

Cited by 39 publications

References 61 publications

Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-κB and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages

Synthetic Vpr Protein Activates Activator Protein-1, c-Jun N-terminal Kinase, and NF-κB and Stimulates HIV-1 Transcription in Promonocytic Cells and Primary Macrophages

ATR and GADD45α mediate HIV-1 Vpr-induced apoptosis

Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells

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