Regulation of matrix metalloproteinase 9 expression by Epstein-Barr virus nuclear antigen 3C and the suppressor of metastasis Nm23-H1.

Abstract

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.

• Authors: Daniel A Kuppers, Ke Lan, Jason S Knight, Erle S Robertson
• Journal: Journal of virology (J Virol) Vol. 79 Issue 15 Pg. 9714-24 (Aug 2005) ISSN: 0022-538X [Print] United States
• PMID: 16014933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Protein Complex 1
• Antigens, Neoplasm
• Carrier Proteins
• Epstein-Barr Virus Nuclear Antigens
• NF-kappa B
• NM23 Nucleoside Diphosphate Kinases
• RNA, Messenger
• SYNRG protein, human
• Gelatin
• NME1 protein, human
• Nucleoside-Diphosphate Kinase
• Matrix Metalloproteinase 9

Topics

• Adaptor Protein Complex 1
• Antigens, Neoplasm (physiology)
• B-Lymphocytes
• Binding Sites (physiology)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Movement
• Epstein-Barr Virus Nuclear Antigens (metabolism, physiology)
• Gelatin
• Herpesvirus 4, Human (physiology)
• Humans
• Matrix Metalloproteinase 9 (genetics, metabolism)
• NF-kappa B (metabolism)
• NM23 Nucleoside Diphosphate Kinases
• Nucleoside-Diphosphate Kinase (metabolism, physiology)
• RNA, Messenger
• Up-Regulation