EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase

Kloster, Martine Müller; Hafte, Tilahun Tolesa; Moltzau, Lise Román; Naderi, Elin Hallan; Dahle, Maria K.; Skålhegg, Bjørn Steen; Gaudernack, Gustav; Levy, Finn Olav; Naderi, Soheil; Blomhoff, Heidi Kiil

doi:10.1016/j.cellsig.2008.02.007

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…In the present study, we have shown that EBV infection down‐regulates the expression of LPAR5 in a number of epithelial cell lines, including five NPC cell lines. These data are consistent with the observation that EBV infection of B cells abrogates the activation of adenylyl cyclase and thereby cAMP formation . Furthermore, we found that the EBV‐encoded oncogene LMP2A can down‐regulate LPAR5 expression in three NPC cell lines.…”

Section: Discussionsupporting

confidence: 92%

Down‐regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV‐associated nasopharyngeal carcinoma

Yap

Velapasamy

Lee

et al. 2014

The Journal of Pathology

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Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.

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Section: Discussionsupporting

confidence: 92%

Down‐regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV‐associated nasopharyngeal carcinoma

Yap

Velapasamy

Lee

et al. 2014

The Journal of Pathology

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“…As described in Table 2, altered expression and/or activity of one or more cyclic nucleotide signaling mediators have been reported in various carcinomas and hematological malignancies [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. The role of cAMP and cGMP signaling and activation of their down-steam effectors (i.e .…”

Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 99%

“…, PKA and PKG) is complex when determining their stimulatory and inhibitory actions in cancer cells. Both cAMP and cGMP signaling have been found to have either positive or negative effects on cell growth and survival, depending on cell or tissue type [40,41,42,43,44,45,46,56,57,58,59,60]. These observations, suggest that aberrant cyclic nucleotide signaling may play an important role in tumorigenesis.…”

Section: Cyclic Nucleotide Signaling In Cancermentioning

confidence: 99%

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Fajardo

Piazza

Tinsley

2014

Cancers

186

169

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For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

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“…There are also viral infections that have an effect on cAMP levels. Infection of B cells by the Epstein-Barr virus blocks the activation of AC and decreased cAMP levels disrupt the control of growth by cAMP-activated PKA, leading to lymphoproliferative disease (Kloster et al, 2008). Hepatocytes infected with the hepatitis C virus show increased cAMP levels but the underlying mechanism in unknown (Farquhar et al, 2008).…”

Section: (6) Bicarbonate Co 2 and Other Triggersmentioning

confidence: 99%

Biological roles of cAMP: variations on a theme in the different kingdoms of life

2013

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Cyclic AMP (cAMP) plays a key regulatory role in most types of cells; however, the pathways controlled by cAMP may present important differences between organisms and between tissues within a specific organism. Changes in cAMP levels are caused by multiple triggers, most affecting adenylyl cyclases, the enzymes that synthesize cAMP. Adenylyl cyclases form a large and diverse family including soluble forms and others with one or more transmembrane domains. Regulatory mechanisms for the soluble adenylyl cyclases involve either interaction with diverse proteins, as happens in Escherichia coli or yeasts, or with calcium or bicarbonate ions, as occurs in mammalian cells. The transmembrane cyclases can be regulated by a variety of proteins, among which the α subunit and the βγ complex from G proteins coupled to membrane receptors are prominent. cAMP levels also are controlled by the activity of phosphodiesterases, enzymes that hydrolyze cAMP. Phosphodiesterases can be regulated by cAMP, cGMP or calcium‐calmodulin or by phosphorylation by different protein kinases. Regulation through cAMP depends on its binding to diverse proteins, its proximal targets, this in turn causing changes in a variety of distal targets. Specifically, binding of cAMP to regulatory subunits of cAMP‐dependent protein kinases (PKAs) affects the activity of substrates of PKA, binding to exchange proteins directly activated by cAMP (Epac) regulates small GTPases, binding to transcription factors such as the cAMP receptor protein (CRP) or the virulence factor regulator (Vfr) modifies the rate of transcription of certain genes, while cAMP binding to ion channels modulates their activity directly. Further studies on cAMP signalling will have important implications, not only for advancing fundamental knowledge but also for identifying targets for the development of new therapeutic agents.

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EBV infection renders B cells resistant to growth inhibition via adenylyl cyclase

Cited by 7 publications

References 44 publications

Down‐regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV‐associated nasopharyngeal carcinoma

Down‐regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV‐associated nasopharyngeal carcinoma

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

Biological roles of cAMP: variations on a theme in the different kingdoms of life

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