Article: article from journal or magazin.
AP-1 and ERK1 but not p38 nor JNK is required for CRPV early protein 2-dependent MMP-9 promoter activation in rabbit epithelial cells.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Human papillomaviruses (HPV) are the known cause for a variety of cancers including cervical and epithelial cancers. The cottontail-rabbit papillomavirus (CRPV) serves as a suitable animal model to study the development of these cancers in vivo. We have previously demonstrated that CRPV-induced skin carcinomas express high levels of MMP-9, a metalloproteinase contributing to cancer progression by extracellular matrix remodelling. Based on our previously reported finding that CRPV early protein 2 can activate a truncated human 670bp MMP-9 promoter fragment, we hypothesized that MMP-9 expression in the rabbit carcinomas is a consequence of activation of the rabbit MMP-9 promoter in-trans by CRPV early protein 2. Further elucidation of the mechanism revealed the requirement for both a proximal and distal AP-1 transcription factor binding site in the rabbit MMP-9 promoter and the AP-1 complex as demonstrated by the inhibitory effect of TAM67, a trans-activation deficient c-jun mutant. The characterization of signal-transduction requirements revealed predominantly ERK1 to be required for CRPV early protein 2-dependent MMP-9 promoter activation, but not JNK nor p38. In summary CRPV early protein 2 activates the expression of MMP-9 in-trans through AP-1 and ERK1 and may contribute to cancer development and progression via this mechanism within the animal model.
Animals, Anthracenes/pharmacology, Binding Sites, Carcinoma/virology, Cell Line, Cell Line, Tumor, Cottontail rabbit papillomavirus/genetics, Cottontail rabbit papillomavirus/physiology, DNA Mutational Analysis, Disease Models, Animal, Enzyme Inhibitors/pharmacology, Epithelial Cells/drug effects, Epithelial Cells/metabolism, Flavonoids/pharmacology, Humans, Imidazoles/pharmacology, JNK Mitogen-Activated Protein Kinases/metabolism, Matrix Metalloproteinase 9/genetics, Matrix Metalloproteinase 9/metabolism, Mitogen-Activated Protein Kinase 3/metabolism, Molecular Sequence Data, Promoter Regions, Genetic/genetics, Pyridines/pharmacology, Rabbits, Signal Transduction, Transcription Factor AP-1/metabolism, Transcription Factors/metabolism, Viral Proteins/metabolism, p38 Mitogen-Activated Protein Kinases/metabolism
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