Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that is involved in many functions, including the inflammatory response, immunity and apoptosis. Some of the responses of TNF-alpha are mediated by caspase-1, which is involved in the production of the pro-inflammatory cytokines interleukin-1beta, interleukin-18 and interleukin-33. The molecular mechanisms involved in TNF-alpha-induced caspase-1 gene expression remain poorly defined, despite the fact that signaling by TNF-alpha has been well studied. The present study was undertaken to investigate the mechanisms involved in the induction of caspase-1 gene expression by TNF-alpha. Treatment of A549 cells with TNF-alpha resulted in an increase in caspase-1 mRNA and protein expression, which was preceded by an increase in interferon regulatory factor-1 and p73 protein levels. Caspase-1 promoter reporter was activated by the treatment of cells with TNF-alpha. Mutation of the interferon regulatory factor-1 binding site resulted in the almost complete loss of basal as well as of TNF-alpha-induced caspase-1 promoter activity. Mutation of the p53/p73 responsive site resulted in reduced TNF-alpha-induced promoter activity. Blocking of p73 function by a dominant negative mutant or by a p73-directed small hairpin RNA reduced basal as well as TNF-alpha-induced caspase-1 promoter activity. TNF-alpha-induced caspase-1 mRNA and protein levels were reduced when p73 mRNA was down-regulated by small hairpin RNA. Caspase-5 gene expression was induced by TNF-alpha, which was inhibited by the small hairpin RNA-mediated down-regulation of p73. Our results show that TNF-alpha induces p73 gene expression, which, together with interferon regulatory factor-1, plays an important role in mediating caspase-1 promoter activation by TNF-alpha.
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PMID:Tumor necrosis factor-alpha-induced caspase-1 gene expression. Role of p73. 1772 14

Malignant melanoma is a highly aggressive and drug-resistant cancer. Virotherapy is a novel therapeutic strategy based on cancer cell lysis through selective virus replication. However, its clinical efficacy is modest, apparently related to poor virus replication within the tumors. We report that the growth compromised herpes simplex virus type 2 (HSV-2) mutant, DeltaPK, has strong oncolytic activity for melanoma largely caused by a mechanism other than replication-induced cell lysis. The ratio of dead cells (determined by trypan blue or ethidium homodimer staining) to cells that stain with antibody to the major capsid protein VP5 (indicative of productive infection) was 1.8-4.1 for different melanoma cultures at 24-72 h post-infection. Cell death was due to activation of calpain as well as caspases-7 and -3 and it was abolished by the combination of calpain (PD150606) and pancaspase (benzyloxycarbonyl-Val-Ala-Asp-fluormethyl ketone, z-VAD-fmk) inhibitors. Upregulation of the autopahgy protein Beclin-1 and the pro-apoptotic protein H11/HspB8 accompanied DeltaPK-induced melanoma oncolysis. Intratumoral DeltaPK injection (10(6)-10(7) plaque-forming unit (pfu)) significantly reduced melanoma tumor burden associated with calpain and caspases-7 and -3 activation, Beclin-1 and H11/HspB8 upregulation and activation of caspase-1-related inflammation. Complete remission was seen for 87.5% of the LM melanoma xenografts at 5 months after treatment termination. The data indicate that DeltaPK is a promising virotherapy for melanoma that functions through virus-induced programmed cell death pathways.
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PMID:The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins. 1979 49