title: Matrix metalloproteinase 9 expression is induced by Epstein-Barr virus latent membrane protein 1 C-terminal activation regions 1 and 2.
abstract: Nasopharyngeal carcinoma (NPC), which is closely associated with the Epstein-Barr virus (EBV), is a highly metastatic malignant tumor. An important activity in tumor invasion and metastasis is that of the 92-kDa type IV collagenase or gelatinase, matrix metalloproteinase 9 (MMP-9), which mediates the degradation of the basement membrane and extracellular matrix. The expression of MMP-9 has been shown to be enhanced by the EBV oncoprotein, latent membrane protein 1 (LMP-1). LMP-1, which is expressed in NPC, has two essential signaling domains within the carboxy terminus, termed C-terminal activation regions 1 (CTAR-1) and CTAR-2. This study reveals that either signaling domain can activate the MMP-9 promoter and induce MMP-9 activity; however, LMP-1 deletion mutants lacking either CTAR-1 or CTAR-2 had a decreased ability to induce MMP-9 expression. The deletion of both activation regions completely abolished the induction of MMP-9 activity, while the cotransfection of both the CTAR-1 and CTAR-2 deletion mutants restored MMP-9 activity to levels produced by wild-type LMP-1. The NF-kappaB and activator protein 1 (AP-1) binding sites in the MMP-9 promoter were essential for the activation of MMP-9 gene expression by both CTAR-1 and CTAR-2. The induction of MMP-9 expression by LMP-1 and both CTAR-1 and CTAR-2 mutants was blocked by the overexpression of IkappaB. The tumor necrosis factor receptor-associated factor (TRAF) pathway also contributed to the activation of the MMP-9 promoter as shown by the use of TRAF-2 and TRAF-3 dominant-negative constructs. These data indicate that the activation of both the NF-kappaB and AP-1 pathways by LMP-1, CTAR-1, and CTAR-2 is necessary for the activation of MMP-9 expression. In NPC, LMP-1 may contribute to invasiveness and metastasis through the induction of MMP-9 transcription and enzymatic activity.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: H
authors.initials: H
authors.lastname: Takeshita
authors.forename: T
authors.initials: T
authors.lastname: Yoshizaki
authors.forename: W E
authors.initials: WE
authors.lastname: Miller
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Furukawa
authors.forename: J S
authors.initials: JS
authors.lastname: Pagano
authors.forename: N
authors.initials: N
authors.lastname: Raab-Traub
mesh_terms: D001665:Binding Sites; D017364:Collagenases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D020780:Matrix Metalloproteinase 9; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010455:Peptides; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins; D017364:Collagenases; D020780:Matrix Metalloproteinase 9