title: Upregulation of equine matrix metalloproteinase 1 by bovine papillomavirus type 1 is through the transcription factor activator protein-1.
abstract: Equine sarcoids represent the most common skin tumours in equids worldwide, characterized by extensive invasion and infiltration of lymphatics, rare regression and high recurrence after surgical intervention. Bovine papillomavirus type 1 (BPV-1) activity is necessary for the transformation phenotype of equine fibroblasts. Among the many changes induced by BPV-1, matrix metalloproteinase 1 (MMP-1) upregulation contributes to the invasiveness of equine fibroblasts. However, it is not yet known how BPV-1 proteins regulate equine MMP-1 expression. To elucidate this mechanism, the equine MMP-1 promoter was cloned and analysed. A putative activator protein-1 (AP-1)-binding site was demonstrated to be crucial for upregulated MMP-1 promoter activity by BPV-1. BPV-1 E6 and E7 proteins increased MMP-1 promoter activity, and inhibition of BPV-1 gene expression by small interfering RNA significantly reduced the promoter activity. c-Jun and Fra-1, two components of the AP-1 transcription factor complex, were overexpressed and activated by BPV-1 in equine fibroblasts. Finally, BPV-1 E5, E6 and E7 proteins increased MMP-1 mRNA and protein expression. In conclusion, the expression of MMP-1 can be enhanced by BPV-1 oncoproteins E6 and E7 through the AP-1 transcription factor and by E5 via an indirect mechanism. These findings shed light on the mechanism of BPV-1-mediated equine fibroblast infiltration and indicate that both BPV-1 oncoproteins and AP-1 could be potential targets for equine sarcoid therapy.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: ZhengQiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gault
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: M Saveria
authors.initials: MS
authors.lastname: Campo
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Garscube Campus, Bearsden Road, Glasgow G61 1QH, UK.
authors.forename: Lubna
authors.initials: L
authors.lastname: Nasir
mesh_terms: D000818:Animals; D001665:Binding Sites; D052688:Bovine papillomavirus 1 / Q000472:pathogenicity*; D002460:Cell Line; D020869:Gene Expression Profiling; D006736:Horses; D054884:Host-Pathogen Interactions; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D009856:Oncogene Proteins, Viral; D018808:Transcription Factor AP-1; C075621:oncogene protein E7, Bovine papillomavirus type 1; C059269:protein E6, Bovine papillomavirus; D020781:Matrix Metalloproteinase 1