J Biol Chem, Vol. 274, Issue 27, 18981-18988, July 2, 1999

3-Deazaadenosine, a S-Adenosylhomocysteine Hydrolase Inhibitor, Has Dual Effects on NF-B Regulation
INHIBITION OF NF-B TRANSCRIPTIONAL ACTIVITY AND PROMOTION OF IB DEGRADATION

Seong-Yun Jeong, Sang-Gun Ahn, Jeong-Hwa Lee, Ho-Shik Kim, Jin-Woo Kim^§, Hyangshuk Rhim^§, Seong-Whan Jeong, and In-Kyung Kim^§

From the  Department of Biochemistry, ^§ Research Institute of Molecular Genetics, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea

Previously we reported that 3-deazaadenosine (DZA), a potent inhibitor and substrate for S-adenosylhomocysteine hydrolase inhibits bacterial lipopolysaccharide-induced transcription of tumor necrosis factor- and interleukin-1 in mouse macrophage RAW 264.7 cells. In this study, we demonstrate the effects of DZA on nuclear factor-B (NF-B) regulation. DZA inhibits the transcriptional activity of NF-B through the hindrance of p65 (Rel-A) phosphorylation without reduction of its nuclear translocation and DNA binding activity. The inhibitory effect of DZA on NF-B transcriptional activity is potentiated by the addition of homocysteine. Taken together, DZA promotes the proteolytic degradation of IB, but not IB, resulting in an increase of DNA binding activity of NF-B in the nucleus in the absence of its transcriptional activity in RAW 264.7 cells. The reduction of IB by DZA is neither involved in IB kinase complex activation nor modulated by the addition of homocysteine. This study strongly suggests that DZA may be a potent drug for the treatment of diseases in which NF-B plays a central pathogenic role, as well as a useful tool for studying the regulation and physiological functions of NF-B.