Journal
JOURNAL OF VIROLOGY
Volume 79, Issue 15, Pages 9714-9724Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.79.15.9714-9724.2005
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Funding
- NCI NIH HHS [R01 CA072150, CA108461, R01 CA108461, R29 CA072150, CA72150-07] Funding Source: Medline
- NIDCR NIH HHS [DE14136-01, R01 DE014136] Funding Source: Medline
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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 NF kappa B 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 NF kappa B transcription factors.
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