Vpr Protein of Human Immunodeficiency Virus Type 1 Binds to 14-3-3 Proteins and Facilitates Complex Formation with Cdc25C: Implications for Cell Cycle Arrest

Kino, Tomoshige; Gragerov, Alexander; Valentı́n, Antonio; Tsopanomihalou, Maria; Ilyina-Gragerova, Galina; Erwin-Cohen, Rebecca; Chrousos, George P.; Pavlakis, George N.

doi:10.1128/jvi.79.5.2780-2787.2005

Cited by 63 publications

(66 citation statements)

References 51 publications

(65 reference statements)

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“…The Rad17 and Hus1 proteins involved in the ATR pathway were shown to be required for cell cycle arrest by Vpr (44). Vpr was also shown to bind Cdc25c directly and inhibit Cdc25c phosphatase activity (43,45), perhaps blocking cyclin B1-Cdc2 redundantly with the ATR pathway. Recently Jacotot et al (19) demonstrated that Vpr-(52-96)-induced apoptosis may occur through a direct effect on the mitochondrial permeability transition pore complex and specifically on the mitochondrial adenine nucleotide translocator, a component of the permeability transition pore complex.…”

Section: Discussionmentioning

confidence: 99%

“…In general, this complex is inactivated by Wee1 kinase and activated by Cdc25c phosphatase (41). Vpr mediates cell cycle arrest by phosphorylation and inactivation of Cdc25c phosphatase via activating the ataxia-telangiectasia and Rad3-related (ATR) DNA damage response pathway (42,43). The Rad17 and Hus1 proteins involved in the ATR pathway were shown to be required for cell cycle arrest by Vpr (44).…”

Section: Discussionmentioning

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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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: 99%

Section: Discussionmentioning

confidence: 99%

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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“…In this scenario, it is possible that the NT-Ago1 protein stabilizes the 14-3-3⅐Cdc25 complex in the cytoplasm independently of the Cdc25 phosphorylation status. Indeed, this is how the Vpr protein of human immunodeficiency virus is thought to delay cell cycle progression at the G 2 /M boundary in mammalian cells by promoting association of 14-3-3 and Cdc25C in a manner that does not require phosphorylation of Cdc25 (35). However, given that we did not observe colocalization between Cdc25-GFP and RFP-NT-Ago1 in the cytoplasm, it seems unlikely that NT-Ago1 functions in a similar manner to Vpr.…”

Section: Discussionmentioning

confidence: 99%

Interactions between the RNA Interference Effector Protein Ago1 and 14-3-3 Proteins

Stoica

Carmichael

Parker

et al. 2006

Journal of Biological Chemistry

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Here, we provide evidence that the amino terminus of Ago1 binds to proteins that function in cell cycle regulation including 14-3-3 proteins. Interestingly, the amino terminus of human Ago2, the endonuclease that cleaves siRNA-targeted mRNAs, was also demonstrated to bind 14-3-3 proteins. Overexpression of the Ago1 amino terminus in yeast resulted in cell cycle delay at the G 2 /M boundary. Further investigation revealed that nuclear import of the mitosis-inducing phosphatase Cdc25 is inhibited by overexpression of the Ago1 amino terminus. Under these conditions, we found that the cyclin-dependent kinase Cdc2 is constitutively phosphorylated on tyrosine 15, thereby reducing the activity of this kinase, a situation that delays entry into mitosis. We hypothesize that 14-3-3 proteins are required for Argonaute protein functions in cell cycle and/or gene-silencing pathways.

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“…The Cdc25 inhibitor rad25 [19], which is a homologue of human 14-3-3 proteins, enhances Vpr-induced G2 arrest when overproduced in fission yeast [39]. Recent studies further show that Vpr binds to Cdc25C and to 14-3-3 in human cells [43][44][45].…”

Section: Cell Cycle G2/m Arrest Induced By Hiv-1 Vprmentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

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Vpr Protein of Human Immunodeficiency Virus Type 1 Binds to 14-3-3 Proteins and Facilitates Complex Formation with Cdc25C: Implications for Cell Cycle Arrest

Cited by 63 publications

References 51 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

Interactions between the RNA Interference Effector Protein Ago1 and 14-3-3 Proteins

Viral infections and cell cycle G2/M regulation

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