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, Audrey; Decrion, Anne Zélie; Sabbah, Emmanuelle N.; Quivy, Vincent; Sire, Joséphine; Lint, Carine Van; Roques, Bernárd P.; Aggarwal, Bharat B.; Herbein, Georges

doi:10.1074/jbc.m502211200

Cited by 68 publications

(78 citation statements)

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“…This event leads to permeabilization of the outer mitochondrial membrane with consequent release of apoptosis-inducing factor and cytochrome c (9,19). Cytochrome c interacts with Apaf-1 and procaspase 9 to create an apoptosome, the caspase activation complex that causes activation of other caspases resulting in apoptosis (8,9,19 (10,48), this is the first report describing a novel pathway involving JNK activation in Vpr-induced apoptosis. The JNK group of MAPKs is encoded by three genes: jnk1 and jnk2 genes, which are ubiquitously expressed, and the jnk3 gene expressed primarily in the heart, testis, and brain (49).…”

Section: Discussionmentioning

confidence: 94%

“…Pretreatment of cells with JNK inhibitors SP60025 and DXM or transfection with JNKspecific siRNAs significantly inhibited Vpr-induced apoptosis. Although MAPKs have been reported to regulate HIV replication in T cells and latently infected cells (10,48), this is the first report describing a novel pathway involving JNK activation in Vpr-induced apoptosis. The JNK group of MAPKs is encoded by three genes: jnk1 and jnk2 genes, which are ubiquitously expressed, and the jnk3 gene expressed primarily in the heart, testis, and brain (49).…”

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confidence: 99%

“…It plays a key role in virus replication by causing nuclear translocation of the HIV-1 preintegration complex and transcriptional regulation of the HIV long terminal repeat (7)(8)(9)(10). It has also been shown to induce cell cycle arrest at the G 2 /M phase and apoptosis in a variety of cell types including T cells, neutrophils, and neuronal cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein (7,11).…”

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Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Mishra

Kumar

2007

Journal of Biological Chemistry

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Human immunodeficiency virus (HIV) accessory protein viral protein R (Vpr) plays a key role in virus replication and induces cell cycle arrest and apoptosis in various cell types including T cells and neuronal and tumor cells following infection withApoptosis is an active process mediated by programmed signaling pathways that can be initiated by a variety of intracellular and extracellular stimuli. Apoptosis is essential to many biological processes including functional self-organizational processes in the immune and central nervous systems, morphogenetic changes in embryonic development, tissue homeostasis, and normal cell turnover (1). It also plays a critical role in the pathogenesis of a variety of diseases including cancer and infectious diseases (1, 2). Modulation of apoptosis may be closely associated with the outcome of a disease process. For example, resistance to apoptosis is one of the important mechanisms by which cancer cells evade destruction by the immune system (1). Therefore, effective therapies against such diseases should ideally induce efficient cytotoxicity to override apoptotic resistance. Recently the viral protein R (Vpr) 3 of the human immunodeficiency virus (HIV) has been proposed as a novel antiproliferative agent in vivo because of its ability to induce apoptosis in normal and tumor cell lines, including leukemialymphoma, colon, and cervical carcinoma cell lines (3, 4), and its ability to transduce cells effectively without carriers or receptor targeting strategies (5, 6).Vpr, a 14-kDa 96-amino acid protein, is the most conserved and multifunctional regulatory protein. It plays a key role in virus replication by causing nuclear translocation of the HIV-1 preintegration complex and transcriptional regulation of the HIV long terminal repeat (7-10). It has also been shown to induce cell cycle arrest at the G 2 /M phase and apoptosis in a variety of cell types including T cells, neutrophils, and neuronal cells following infection with Vpr-expressing HIV isolates or exposure to the extracellular Vpr protein (7,11). Recently Vpr was detected in the sera and cerebrospinal fluid of HIV-infected subjects at levels similar to those of p24 antigen (5, 12). Moreover circulating Vpr was found to be biologically active in inducing virion production from latently infected cells, inducing apoptosis and causing depletion of bystander cells in lymphoid tissues during HIV infection (5,12).Multiple functions of Vpr have been attributed to its different domains (13). The Vpr protein is characterized by three well defined ␣-helices: 17-33, 40 -48, and 55-83 surrounded by flexible negatively charged N-terminal and basic C-terminal * This work was supported in part by grants from the Canadian Institutes of Health Research (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 (14). Furthermore the amphipathic ␣-helix 55-83...

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

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confidence: 99%

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Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Mishra

Kumar

2007

Journal of Biological Chemistry

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“…Thus, NF-κB is increasingly considered as a target for anti-cancer drug treatment (23)(24)(25)(26)(27). Many studies have demonstrated that Vpr was able to block NF-κB activation (37,38), whereas others reported that Vpr may also activate NF-κB and protect cells from apoptosis (18,39). However, in the current study, we further confirmed that Ad-Vpr was able to inhibit NF-κB activation in a time-dependent manner through the upregulation of IκBα in the cytoplasm, and inhibition of nuclear translocation of p65 and DNA-binding activity of p65.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the Vpr protein appears to preferentially inhibit the growth of rapidly dividing tumor cells, but does not affect the normal cells regardless of changes in p53 expression (7)(8)(9)15). Most importantly, the Vpr protein can easily penetrate the cell membrane without the help of a receptor or carrier (16)(17)(18) …”

Section: Introductionmentioning

confidence: 99%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

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Abstract. Colorectal cancer is a significant health problem, and the advanced stages of the disease have a low response rate to chemotherapy and easily acquire chemoresistance. HIV-1 viral protein R (Vpr) has been shown to possess inhibitory effects on various malignant cells in vivo and in vitro. In this study, an Ad-Vpr construct was used to infect the multidrug-resistant human colorectal cancer HCT-8/5-FU(MDR) cell line in vitro for cell viability, apoptosis, gene expression and gene activity using the MTT, flow cytometry, immunoblotting and gel shift assays, respectively. The data showed that Ad-Vpr significantly reduced HCT-8/5-FU(MDR) cell viability in a dose-and time-dependent manner. Ad-Vpr infection promoted HCT-8/5-FU(MDR) cells to undergo apoptosis and to arrest at the G2 phase of the cell cycle. The G2 cell cycle protein Cyclin B1 accumulated in the cells after Ad-Vpr infection. Furthermore, Ad-Vpr induced activation of caspase-3 and -9, but not caspase-8, in HCT-8/5-FU(MDR) cells. Ad-Vpr suppressed expression of the Bcl-xl protein, but upregulated Bax expression and cytochrome c release from the mitochondria in HCT-8/5-FU(MDR) cells. Ad-Vpr infection also resulted in a time-dependent decrease in nuclear translocation of NF-κB/p65 protein and p65 DNA-binding activity in HCT-8/5-FU(MDR) cells. The data from the current study provide mechanistic insights into understanding the molecular basis and utility of Ad-Vpr as a novel anticancer agent for multidrug resistance in human colorectal cancer. IntroductionColorectal cancer is a significant health problem in the world, and is the third most common cancer in women and the fourth most common in men. More than half a million patients with colorectal cancer die of the disease annually worldwide (1,2). To date, surgical intervention is the most effective tool to cure colorectal cancer, whereas chemotherapy is another important means to treat colorectal cancer, especially for advanced staged disease. In those patients, chemotherapy appears to be the only therapeutic modality and offers some benefit. For chemotherapy, 5-fluorouracil (5-FU)-based regimens are the most common choice for patients. The combination of 5-FU with irinotecan and oxaliplatin has significantly improved the response rate of colorectal cancer patients. Additionally, combination regimens of 5-FU with irinotecan have been evaluated as the first-line therapeutic selection for advanced colorectal cancer with a response rate of 30-50% and an overall survival of 14-20 months (3,4). However, the response rate for these advanced targeted therapies and third-generation chemotherapies remains low (5). The reason may be due to innate and acquired chemoresistance (6) of colorectal cancer, which often leads to relapse and poor patient prognosis. Thus, a more aggressive and effective therapy to control colorectal cancer is imperative.To this end, our research focuses on the viral protein R (Vpr), which is an accessory protein and plays an important role in the regulation of nuclear import of the HIV-1 ...

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Inhibition of NF‐κB activity by HIV‐1 Vpr is dependent on Vpr binding protein

Kogan

Deshmane

Sawaya

et al. 2012

Journal Cellular Physiology

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Numerous studies have reported that Vpr alters NF-κB signaling in various cell types, however, the findings have been largely conflicting with reports of both stimulatory and inhibitory effects of Vpr. Our aim was to investigate the role of Vpr signaling in myeloid cells using an adenovirus based expression and indicator system. Our results show that Vpr is inhibitory to NF-κB, however, this effect is dependant on the particular manner of NF-κB stimulation. Consistent with this notion, we report that Vpr has inhibitory effects that are specific to the TNF-α pathway, but not affecting the LPS pathway, suggesting that differential targets of Vpr may exist for NF-κB regulation. Further, we identify VprBP as one possible cellular component of Vpr’s regulation of IκBα in response to TNF-α stimulation. We did not identify such a role for HSP27, which instead seems to inhibit Vpr functions. Chronically HIV-1 infected U1 cells with knockdown constructs for Vpr were unexpectedly less responsive to TNF-α mediated viral replication, perhaps suggesting that other HIV-1 components may antagonize these anti-NF-κB effects in infected cells. We hypothesize that Vpr may serve an important role in the context of viral infection and immune function in vivo, through its selective inhibition of NF-κB pathways.

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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

Abstract: The human immunodeficiency virus (HIV)Vpr

Cited by 68 publications

References 85 publications

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

Activation of JNK-dependent Pathway Is Required for HIV Viral Protein R-induced Apoptosis in Human Monocytic Cells

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Inhibition of NF‐κB activity by HIV‐1 Vpr is dependent on Vpr binding protein

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