HIV-1 Tat Induces Microvascular Endothelial Apoptosis Through Caspase Activation

Park, In-Woo; Ullrich, Christina; Schoenberger, Elena S.; Ganju, Ramesh K.; Groopman, Jerome E.

doi:10.4049/jimmunol.167.5.2766

Cited by 71 publications

(67 citation statements)

References 24 publications

(23 reference statements)

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“…Other RNA viruses encode more than one protein that induce apoptosis. Proteases 2A and 3C of poliovirus, envelope glycoproteins E1 and E2 of Sindbis virus, and four proteins of human immunodeficiency virus, gp120, gp41, Tat, and Vpr, induce apoptosis (1,8,9,14,16,22,39). While it is uncertain why viruses have more than one protein that induce apoptosis, different proteins may provide selective advantage for a virus in different environments.…”

Section: Discussionmentioning

confidence: 99%

Langat Flavivirus Protease NS3 Binds Caspase-8 and Induces Apoptosis

Prikhod'ko¹,

Prikhod’ko

Pletnev³

et al. 2002

J Virol

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The flavivirus NS3 protein plays an important role in the cleavage and processing of the viral polyprotein and in the synthesis of the viral RNA. NS3 recruits NS2B and NS5 proteins to form complexes possessing protease and replicase activities through protease and nucleoside triphosphatase/helicase domains. We have found that NS3 also induces apoptosis. Expression of the Langat (LGT) virus NS3 protein resulted in a cleavage of cellular DNA and reduced the viability of cells. Coexpression of NS3 with apoptotic inhibitors (CrmA and P35) and addition of caspase peptide substrates (Z-VAD-FMK and Z-IETD-FMK) to NS3-transfected cells blocked NS3-induced apoptosis. In cotransfection experiments, NS3 bound to caspase-8 and enhanced caspase-8-mediated apoptosis. NS3 and caspase-8 colocalized in the cytoplasm of transfected cells. Deletion analysis demonstrated that at least two regions of NS3 contribute to its apoptotic activities. The protease and helicase domains are each able to bind to caspase-8, while the protease domain alone induces apoptosis. The protease domain and tetrahelix region of the helicase domain are required for NS3 to augment caspase-8-mediated apoptosis. Thus, the LGT virus NS3 protein is a multifunctional protein that binds to caspase-8 and induces apoptosis.The Flavivirus genus includes mostly arthropod-borne pathogens, many of which are widely distributed throughout the world and cause human diseases that vary in severity. The four serotypes of dengue (DEN) virus, Japanese encephalitis (JE) virus, and yellow fever (YF) virus cause millions of cases of disease annually in the tropics and subtropics. Tick-borne encephalitis (TBE) flaviviruses grouped within the TBE complex (Russian spring-summer encephalitis or TBE, Kyasanur forest disease, Langat [LGT], Louping ill, Negishi, Omsk hemorrhagic fever, and Powassan viruses) are mainly found in the Northern Hemisphere and, except for LGT virus, cause thousands of human cases every year, which can have a mortality as high as 20 to 30%.LGT virus does not naturally infect humans and has been studied as a potential live virus vaccine to protect against encephalitis caused by viruses of the TBE complex (4).LGT virus, like other flaviviruses, is a small lipid-enveloped, positive-sense RNA virus. During infection, a single polycistronic viral RNA is translated into a polyprotein precursor that is co-and posttranslationally processed by host and viral proteases to produce the virion and replicase components. The structural proteins of flaviviruses, capsid (C), premembrane (preM), and envelope (E), are encoded in the 5Ј quarter of the genome, and signal peptidase appears to mediate their cleavages during elongation of the polyprotein precursor through the translocating channel of the rough endoplasmic reticulum. Nonstructural proteins NS2A and -B, NS3, NS4A and -B, and NS5 are cleaved by viral serine protease NS2B-NS3 after a sequence that usually contains two basic residues followed by a short side chain residue (reviewed in reference 19).NS3 protein exhibits p...

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Section: Discussionmentioning

confidence: 99%

Langat Flavivirus Protease NS3 Binds Caspase-8 and Induces Apoptosis

Prikhod'ko¹,

Prikhod’ko

Pletnev³

et al. 2002

J Virol

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“…HIV-1 viral products can be released by infected microglia and astroglia (Ensoli et al, 1990;Munis et al, 1992;Robert-Guroff et al, 1990;Chang et al, 1997;Shutt and Soil, 1999;Jones et al, 1998;Jones et al, 2000), and can also induce the production and release of proinflammatory cytokines and cellular toxins in neural cells (Yeung et al, 1995;Adamson et al, 1996;Bagetta et al, 1996a;Kaul and Lipton, 1999;Nath et al, 1999). Numerous lines of evidence suggest that extracellular proinflammatory cytokines and cellular toxins can induce neuronal apoptosis (Gabuzda et al, 1986;Gendelman et al, 1994;Shi et al, 1998;New et al, 1998;Bagetta et al, 1999;Holden et al, 1999;Zheng et al, 1999;Park et al, 2001;Takahashi et al, 1996). Furthermore, several studies suggest that HIV-1 Tat and gp120 interact with neuronally-expressed receptors to activate multiple pro-apoptotic signaling cascades in neurons Moore et al, 1997;New et al, 1997;Shi et al, 1998;Piller et al, 1999;Bonavia et al, 2001;Corasaniti et al, 2001;Haughey et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…HIV encephalitis (HIVE) often accompanies HIV dementia and is characterized by prominent microglial activation, neuronal losses, dendritic pruning, and decreased density of synapses (Masliah et al, 1996;Lipton, 1997). Apoptotic changes are seen with HIVE in both neurons and nonneuronal cells (Ramirez et al, 2001;Bonavia et al, 2001;Corasaniti et al, 2001;AdleBiassette et al, 1995;Gelbard et al, 1995;Petito and Roberts, 1995;Shi et al, 1996;Kaul et al, 2001;Shi et al, 1998;Park et al, 2001). HIV-1 is neurotoxic by inducing inflammation and through the direct release of toxic viral proteins such as Nef, Vpr, gp120 and Tat (Haughey et al, 2001;Brenneman et al, 1988;Dreyer et al, 1990;Adamson et al, 1996;New et al, 1997;Kruman et al, 1998;Yeung et al, 1998;Huang and Bond, 2000;Trillo-Pazos et al, 2000;Nath, 2002).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

et al. 2004

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“…The level of chromatin cleavage due to apoptosis was quantitated by using the Fluorescein In Situ Cell Death Detection kit (Roche, IN, USA), as described (Park et al, 2001). To assess caspase-3-mediated apoptosis, a cell-permeable, irreversible inhibitor of caspase-3, Z-DEVD-FMK (R&D Systems, Minneapolis, MN, USA), and FMK-control (R&D Systems) were employed.…”

Section: Tunel Assaymentioning

confidence: 99%

“…Cells stimulated with the indicated compounds were lysed in radioimmunoprecipitation assay buffer, and immunoblot analyses were performed, as described (Park et al, 2001).…”

Section: Immunoblot Analysesmentioning

confidence: 99%

Evaluation of novel cell cycle inhibitors in mantle cell lymphoma

Park

Reddy

et al. 2007

Oncogene

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Signature abnormalities in the cell cycle and apoptotic pathway have been identified in mantle cell lymphoma (MCL), affording the opportunity to develop targeted therapies. In this study, we tested a novel class of kinase inhibitors, styryl sulfones, which differ from prior cell cycle inhibitors in that they are not related to purines or pyrimidines. We observed that two closely related compounds, ON013100 and ON01370, altered the growth and cell cycle status of MCL lines and potently inhibited the expression of several important molecules, including cyclin-dependent kinase4, p53, mouse double minute 2 (MDM2), and cyclin D as well as increased cyclin B expression. Using both terminal deoxy transferase uridine triphosphate nick end-labelling and poly ADP-ribose polymerase assays, we found that these compounds caused apoptosis in MCL cells. In addition, using molecular analyses, we observed the modulation of caspase-3 activity but not the expression of B-cell lymphoma family molecules. Next, we investigated the cytotoxicity of the MCL lines upon treatment with styryl sulfone compounds in combination with other currently used chemotherapeutic agents, such as doxorubicin (DOX) or vincristine (VCR). We found that the combination of DOX plus styryl sulfone or VCR plus styryl sulfone increased cytotoxicity by one log scale, compared with the single styryl sulfone compound. Thus, styryl sulfones alone, or in combination with chemotherapeutic agents, present attractive opportunities for new drug development in MCL.

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HIV-1 Tat Induces Microvascular Endothelial Apoptosis Through Caspase Activation

Cited by 71 publications

References 24 publications

Langat Flavivirus Protease NS3 Binds Caspase-8 and Induces Apoptosis

Langat Flavivirus Protease NS3 Binds Caspase-8 and Induces Apoptosis

Apoptotic death of striatal neurons induced by human immunodeficiency virus-1 Tat and gp120: Differential involvement of caspase-3 and endonuclease G

Evaluation of novel cell cycle inhibitors in mantle cell lymphoma

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