Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herpes simplex virus type 1 (HSV-1) primarily infects mucoepithelial tissues of the eye, the orofacial region, and to a lesser extent the genitalia. The virus is retrogradely transported through the axons of sensory and sympathetic neurons to their cell bodies to establishe a life-long latent infection. Throughout this latency period, the viral genome is transcriptionally silent except for a single region encoding the latency-associated transcript (LAT). The function of LAT is still largely unknown. To understand how HSV-1 latency might affect neurons, the authors transfected primary cultures of sympathetic neurons and trigeminal sensory neurons obtained from rat embryos with LAT-expressing plasmids. LAT increased the survival of both sympathetic and trigeminal neurons after induction of cell death by nerve growth factor (NGF) deprivation. Because HSV-1 is transported through axons both after initial infection and during reactivation, the authors considered the possibility that LAT may affect axonal growth. They found that LAT expression increased axonal regeneration by twofold in both types of neurons. Inhibition of the mitogen-activated protein kinase (MAPK) pathway reverses stimulation of both neuronal survival and axonal regeneration, which indicates that these effects are mediated through the MAPK pathway. These data provide evidence that HSV-1 LAT promotes survival of sympathetic as well as trigeminal neurons. The authors show for the first time that LAT stimulates axonal regeneration in both sympathetic and trigeminal neurons.
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PMID:The latency-associated transcript of herpes simplex virus type 1 promotes survival and stimulates axonal regeneration in sympathetic and trigeminal neurons. 1745 49

The N-terminus of the ICP10 gene of type 2 herpes simplex virus (HSV-2) encodes a serine/threonine protein kinase (PK) domain that facilitates HSV-2 replication by activating the Ras/MEK/MAPK mitogenic pathway and suppressing apoptosis. We recently demonstrated that deletion of this oncogenic PK domain converts it to a potent oncolytic agent. This mutant, which we have designated FusOn-H2, preferentially replicates in and thus lyses tumor cells in which the Ras signaling pathway is constitutively activated. Here we show that FusOn-H2 exerts strong ability in inducing apoptosis in different lines of human tumor cells and in esophageal tumors growing in mice. The apoptotic effect produced by FusOn-H2 was not restricted to infected cells but extended to uninfected bystander cells, thereby increasing the lethality of the virus. These results add a novel killing mechanism to those previously assigned to FusOn-H2, rendering it an attractive candidate for clinical trials.
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PMID:An HSV-2-based oncolytic virus deleted in the PK domain of the ICP10 gene is a potent inducer of apoptotic death in tumor cells. 1753 37

Injury caused by distention of the arterial wall by balloon angioplasty can result in apoptosis and vascular smooth muscle cell proliferation. Here, we report that a brief exposure of the arterial lumen to a genetically engineered, attenuated herpes simplex virus 1 blocks activation of caspase 3-dependent apoptosis and MAPK-dependent cell proliferation induced by carotid artery balloon angioplasty and ligation to reduce blood flow. The procedure enables the restoration of the endothelial cell layer lining the lumen and prevents neointimal hyperplasia and restenosis. These findings have a broad application in prevention of balloon angioplasty-induced restenosis.
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PMID:Attenuated herpes simplex virus 1 blocks arterial apoptosis and intimal hyperplasia induced by balloon angioplasty and reduced blood flow. 1762 87

Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-kappaB activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.
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PMID:Herpes simplex virus remodels T-cell receptor signaling, resulting in p38-dependent selective synthesis of interleukin-10. 1780 1

Deltagamma(1)34.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of gamma(1)34.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors.
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PMID:Systemic delivery of (gamma1)34.5-deleted herpes simplex virus-1 selectively targets and treats distant human xenograft tumors that express high MEK activity. 1780 45

The herpes simplex virus type 2 (HSV-2) protein ICP10PK has anti-apoptotic activity in virus-infected hippocampal cultures through activation of the Ras/Raf-1/MEK/ERK pathway. To exclude the possible contribution of other viral proteins to cell fate determination, we examined the survival of primary hippocampal cultures and neuronally differentiated PC12 cells transfected with ICP10PK from apoptosis caused by nerve growth factor (NGF) withdrawal. NGF deprivation caused apoptosis in cultures mock-transfected or transfected with the kinase-negative ICP10 mutant p139(TM), but not in ICP10PK-transfected cultures. In one clone (PC47), ICP10PK inhibited caspase-3 activation through up-regulation/stabilization of adenylate cyclase (AC), activation of PKA and MEK, and the convergence of the two pathways on extracellular signal-regulated kinase activation. The anti-apoptotic proteins Bag-1 and Bcl-2 were stabilized and the pro-apoptotic protein Bad was phosphorylated (inactivated). In another clone (PC70), ICP10PK inhibited apoptosis through MEK-dependent up-regulation of the anti-apoptotic protein XIAP (that inhibits the activity of processed caspase-3) and down-regulation of the apoptogenic protein Smac/DIABLO. This may be cell-type specific, but the baculovirus p35 protein did not potentiate the neuroprotective activity of ICP10PK in PC12 cells, suggesting that ICP10PK inhibits both caspase activation and activity. The data indicate that ICP10PK inhibits apoptosis independent of other viral proteins and is a promising neuronal gene therapy platform.
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PMID:The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation. 1787 40

Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the gamma134.5 gene are promising therapies for cancer. Deltagamma134.5 mutant replication and cytolysis is tumor cell type specific and severely attenuated in normal tissues. The basis for attenuation lies in the activation of the protein kinase R (PKR)-mediated host cellular defense pathway, which inhibits protein synthesis in infected cells. Tumor cells which overexpress MAPK kinase (MEK) activity support robust replication of Deltagamma134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of gamma(1)34.5 mutants may allow selective targeting and destruction of metastases from a broad range of solid human tumors that overexpress MEK. Barriers to systemic HSV-1 oncolytic therapy include innate immunity, adaptive immunity and hepatic adsorption. Immunomodulating agents may overcome innate immunity to HSV-1-based vectors. Preclinical data combined with the pervasiveness of HSV-1 despite widespread immunity suggest that preexisting immunity may not eliminate oncolytic efficacy. In the future, biopsy-determined tumor MEK status may select patients for Deltagamma134.5 oncolytic therapy.
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PMID:Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application. 1792 20

To dissect the molecular basis of the neuroimmune response associated with the genesis of inflammatory (nociceptive) pain, we constructed a herpes simplex virus-based gene transfer vector to express the antiinflammatory cytokine interleukin-10 (IL-10), and used it to examine the effect of IL-10 expression in activated microglial cells in vitro, and in inflammatory pain in vivo. IL-10 reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and decreased the expression of full-length membrane spanning tumor necrosis factor-alpha (mTNFalpha) following lipopolysaccharide stimulation of microglia in vitro. IL-10 also reduced intracellular cleavage of mTNFalpha and release of the soluble cleavage product sTNFalpha. Similar effects on TNFalpha expression were observed when the cells were pretreated with a p38 MAPK inhibitor. In animals, injection of a dilute solution of formalin in the skin resulted in an increase in mTNFalpha in spinal dorsal horn, without detectable sTNFalpha. Local release of IL-10 achieved by gene transfer reduced the number of spontaneous flinches in the early and delayed phases of the formalin test of inflammatory pain. The effect of IL-10 on nocisponsive behavior correlated with a block in phosphorylation of p38 and reduced expression of 26 kDa mTNFalpha in spinal microglia. The results emphasize the key role played by membrane TNFalpha in the spinal neuroimmune response in pain caused by peripheral inflammation.
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PMID:HSV-mediated transfer of interleukin-10 reduces inflammatory pain through modulation of membrane tumor necrosis factor alpha in spinal cord microglia. 1803 11

Gene expression profiling of neuronally-differentiated (ND)-PC12 cells quiescently infected (QIF) with herpes simplex virus type 1 (HSV-1) was performed to determine the response of neuronal cells to long-term maintenance of a non-replicating viral genome independent of the heterogeneous response that occurs in latently infected ganglia. Quiescent infections were characterized by 606 up-regulated and 821 down-regulated cellular genes (P<0.005) compared to parallel, identically treated, mock-infected cultures. Gene ontology analyses suggested that up-regulated cellular genes were involved in steroid biosynthesis and mitogen-activated protein kinase signaling pathways and significantly overrepresented for transcription factor and transcription regulatory functions. Many of the most up-regulated cellular genes encode for proteolytic enzymes involved in neurite outgrowth/axon remodeling. Genes involved in DNA and nucleotide metabolism and apoptosis tended to be down-regulated. These findings demonstrate that a quiescent HSV-1 infection significantly alters neuronal gene expression in ways that may promote survival of the host cell and maintenance of latency.
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PMID:Herpes simplex virus type 1 modulates cellular gene expression during quiescent infection of neuronal cells. 1854 18

The Na(V)1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform plays a critical role in nociception. In rodent models of diabetic neuropathy, increased Na(V)1.7 in dorsal root ganglia (DRG) neurons correlates with the emergence of pain-related behaviors characteristic of painful diabetic neuropathy (PDN). We examined the effect of transgene-mediated expression of enkephalin on pain-related behaviors and their biochemical correlates in DRG neurons. Transfection of DRG neurons by subcutaneous inoculation of a herpes simplex virus-based vector expressing proenkephalin reversed nocisponsive behavioral responses to heat, cold, and mechanical pressure characteristic of PDN. Vector-mediated enkephalin production in vivo prevented the increase in DRG Na(V)1.7 observed in PDN, an effect that correlated with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC). Primary DRG neurons in vitro exposed to 45 mm glucose for 18 h also demonstrated an increase in Na(V)1.7 and increased phosphorylation of p38 and PKC; these changes were prevented by transfection in vitro with the enkephalin-expressing vector. The effect of hyperglycemia on Na(V)1.7 production in vitro was mimicked by exposure to PMA and blocked by the myristolated PKC inhibitor 20-28 or the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]; the effect of vector-mediated enkephalin on Na(V)1.7 levels was prevented by naltrindole. The results of these studies suggest that activation of the presynaptic delta-opioid receptor by enkephalin prevents the increase in neuronal Na(V)1.7 in DRG through inhibition of PKC and p38. These results establish a novel interaction between the delta-opioid receptor and voltage-gated sodium channels.
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PMID:Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. 1857 38


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