Role of Protein Kinase C δ in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Deutsch, Einat; Cohen, Adina; Kazimirsky, Gila; Dovrat, Sara; Rubinfeld, Hadara; Brodie, Chaya; Sarid, Ronit

doi:10.1128/jvi.78.18.10187-10192.2004

Cited by 41 publications

(37 citation statements)

References 69 publications

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“…There is a requirement for another PKC isoform that induces the phosphorylation of c-Jun. c-Fos and c-Jun can then form an active AP-1 complex and induce KSHV reactivation (13,16). Notably, overexpression of PKC␦ alone can induce Zp activity and EBV reactivation in our situation.…”

Section: Discussionmentioning

confidence: 58%

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Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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Epstein-Barr virus (EBV) undergoes latent and lytic replication cycles, and its reactivation from latency to lytic replication is initiated by expression of the two viral immediate-early transactivators, Zta and Rta. In vitro, reactivation of EBV can be induced by anti-immunoglobulin, tetradecanoyl phorbol acetate, and histone deacetylase inhibitor (HDACi). We have discovered that protein kinase C delta (PKC␦) is required specifically for EBV reactivation by HDACi. Overexpression of PKC␦ is sufficient to induce the activity of the Zta promoter (Zp) but not of the Rta promoter (Rp). Deletion analysis revealed that the ZID element of Zp is important for PKC␦ activation. Moreover, the Sp1 putative sequence on ZID is essential for PKC␦-induced Zp activity, and the physiological binding of Sp1 on ZID has been confirmed. After HDACi treatment, activated PKC␦ can phosphorylate Sp1 at serine residues and might result in dissociation of the HDAC2 repressor from ZID. HDACi-mediated HDAC2-Sp1 dissociation can be inhibited by the PKC␦ inhibitor, Rotterlin. Furthermore, overexpression of HDAC2 can suppress the HDACi-induced Zp activity. Consequently, we hypothesize that HDACi induces PKC␦ activation, causing phosphorylation of Sp1, and that the interplay between PKC␦ and Sp1 results in the release of HDAC2 repressor from Zp and initiation of Zta expression.Epstein-Barr virus (EBV), a human oncogenic virus, infects two types of human cells predominantly, B lymphocytes and epithelial cells, and EBV infection also is associated with an array of malignancies derived from these two cell types, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma (49). Being a human gammaherpesvirus, EBV undergoes two cycles: latency and lytic replication. Although most latent products are important for its ability to immortalize cells, and the virus is present in a latent form in most EBV-associated cancer tissues, serological studies revealed that elevated antibody titers against some lytic antigens, or increased viral DNA load in serum, are risk factors for tumor development (8,33). In addition, experiments using the SCID mouse model suggested that Zta, an EBV lytic transactivator, is crucial for tumor formation (43). In vitro, experimental approaches also revealed that EBV lytic products may contribute to the pathogenesis of EBV-associated diseases, via upregulation of cytokines, cell growth factors or antiapoptotic proteins (5, 48, 50). Thus, the reactivation of EBV not only leads to the production of viral progeny but also facilitates viral pathogenesis.In vitro, EBV persists predominantly in a latent form in host cells. However, lytic replication can be elicited conditionally by many different chemicals and physical stimuli or by ectopic transfection with two transactivators, Zta or Rta (49). These inducing agents provide the best available models for the study of essential factors involved in the switch of EBV from latency to lytic replication. Tetradecanoyl phorbol acetate (TPA) and anti-Ig are...

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Section: Discussionmentioning

confidence: 58%

“…In Kaposi's sarcoma herpesvirus infection, PKC␦ is required for TPA-triggered lytic cycle activation (16). However, the overexpression of PKC␦ alone is not sufficient to induce lytic reactivation of KSHV because it can activate c-Fos only partially.…”

Section: Discussionmentioning

confidence: 99%

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Tsai

Lin

Weng

et al. 2011

J Virol

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“…al. (13). On the other hand, the PKC pathway does not appear to be important for n-butyrate or bacterial metabolic end-product-mediated viral reactivation.…”

Section: Resultsmentioning

confidence: 97%

Signaling Cascades Triggered by Bacterial Metabolic End Products during Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Morris

Arnold

Webster-Cyriaque

2007

J Virol

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The present studies explore the role of polymicrobial infection in the reactivation of Kaposi's sarcomaassociated herpesvirus (KSHV) and analyze signaling pathways activated upon this induction. We hypothesized that activation of the cellular stress-activated mitogen-activated protein kinase (MAPK) p38 pathway would play a key role in the bacterium-mediated disruption of viral latency similar to that of previously reported results obtained with other inducers of gammaherpesvirus lytic replication. KSHV within infected BCBL-1 cells was induced to replicate following exposure to metabolic end products from gram-negative or -positive bacteria that were then simultaneously exposed to specific inhibitors of signal transduction pathways. We have determined that bacterium-mediated induction of lytic KSHV infection is significantly reduced by the inhibition of the p38 MAPK pathway. In contrast, inhibition of the phosphatidylinositol 3-kinase pathway did not impair induction of lytic replication or p38 phosphorylation. Protein kinase C, though activated, was not the major pathway used for bacterium-induced viral reactivation. Furthermore, hyperacetylation of histones 3 and 4 was detected. Collectively, our results show that metabolic end products from these pathogens induce lytic replication of KSHV in BCBL-1 cells primarily via the activation of a stress-activated MAPK pathway. Importantly, we demonstrate for the first time a mechanism by which polymicrobial bacterial infections result in KSHV reactivation and pathogenesis.

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“…26). PKCq and PKCq kinase-dead mutants were first cloned into the pShuttle-CMV vector as previously described for PKCy (27). Cells were incubated with a multiplicity of infection of 5 at the appropriate recombinant adenovirus vectors for 1 hour.…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase C-ε Regulates the Apoptosis and Survival of Glioma Cells

et al. 2005

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In this study, we examined the role of protein kinase C (PKC)-E in the apoptosis and survival of glioma cells using tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCE expression. Treatment of glioma cells with TRAIL induced activation, caspasedependent cleavage, and down-regulation of PKCE within 3 to 5 hours of treatment. Overexpression of PKCE inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCE mutant (D383A) was more protective than PKCE, suggesting that both the cleavage of PKCE and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCE in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCE and found that silencing of PKCE expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCE, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCE did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH 2 -kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCE. Our results suggest that the cleavage of PKCE and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCE regulates AKT expression and is essential for the survival of glioma cells. (Cancer Res 2005; 65(16): 7301-9)

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Role of Protein Kinase C δ in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Cited by 41 publications

References 69 publications

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation

Signaling Cascades Triggered by Bacterial Metabolic End Products during Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Protein Kinase C-ε Regulates the Apoptosis and Survival of Glioma Cells

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