Regulation of matrix metalloproteinase 9 expression by Epstein-Barr virus nuclear antigen 3C and the suppressor of metastasis Nm23-H1.
Epstein-Barr virus latent protein EBNA3C has been shown to bind Nm23-H1, a known suppresser of cell migration and metastasis and a regulator of the guanine exchange factor Tiam-1. This interaction results in cellular translocation of Nm23-H1 to the nucleus and suppression of the antimigratory effect in vitro. Furthermore, these proteins can synergistically increase transcription of a basal promoter when targeted to DNA by fusion to a Gal4 DNA binding domain. In this report, we show that EBNA3C and Nm23-H1 can cooperate to upregulate expression of MMP-9, known to be expressed in aggressive forms of lymphomas. This upregulation resulted in increased levels of MMP-9 mRNA, as well as a detectable increase in MMP-9 gelatinolytic activity. Specific mutations in the MMP-9 promoter showed that the Ap1 and NFkappaB binding sites are important for upregulation by the proteins. Additionally, it was shown for the first time that EBNA3C and Nm23-H1 can bind subunits of these transcription factors. This suggests that the ability of EBNA3C to reverse the antimigratory effects of Nm23-H1 is likely to be in part through the synergistic upregulation of MMP-9, mediated through interactions with the AP1 and NFkappaB transcription factors.
Kuppers
Daniel A
DA
Department of Microbiology, Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Lan
Ke
K
Knight
Jason S
JS
Robertson
Erle S
ES
D033961:Adaptor Protein Complex 1; D000951:Antigens, Neoplasm / Q000502:physiology*; D001402:B-Lymphocytes; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism / Q000502:physiology*; D005780:Gelatin; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger; D015854:Up-Regulation
D033961:Adaptor Protein Complex 1; D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D054778:NM23 Nucleoside Diphosphate Kinases; D012333:RNA, Messenger; C121510:SYNRG protein, human; D005780:Gelatin; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020780:Matrix Metalloproteinase 9