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J. Cell Sci. 121 (9): 1466-1476

Research Article

Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide

Mi-Yeon Kim1,*, Ji-Hye Park1,*, Jung-Soon Mo1, Eun-Jung Ann1, Seung-Ok Han1, Sang-Hyun Baek1, Kyoung-Jin Kim2, Suhn-Young Im2, Jeen-Woo Park3, Eui-Ju Choi4, and Hee-Sae Park1,{ddagger}

1 Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Buk-ku, Gwangju, 500-757, Republic of Korea
2 Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Yongbong-dong, Buk-ku, Gwangju, 500-757, Republic of Korea
3 Department of Biochemistry, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea
4 School of Life Science and Biotechnology, Korea University, Seoul, Republic of Korea

{ddagger} Author for correspondence (e-mail: proteome{at}

Accepted for publication 13 February 2008.

Abstract: The Notch signaling pathway appears to perform an important function in inflammation. Here, we present evidence to suggest that lipopolysaccharide (LPS) suppresses Notch signaling via the direct modification of Notch by the nitration of tyrosine residues in macrophages. In the RAW264.7 macrophage cell line and in rat primary alveolar macrophages, LPS was found to inhibit Notch1 intracellular domain (Notch1-IC) transcription activity, which could then be rescued by treatment with N(G)-nitro-l-arginine, a nitric oxide synthase (NOS) inhibitor. Nitric oxide (NO), which was produced in cells that stably express endothelial NOS (eNOS) and brain NOS (bNOS), also induced the inhibition of Notch1 signaling. The NO-induced inhibition of Notch1 signaling remained unchanged after treatment with 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), a guanylyl-cyclase inhibitor, and was not found to be mimicked by 8-bromo-cyclic GMP in the primary alveolar macrophages. With regards to the control of Notch signaling, NO appears to have a significant negative influence, via the nitration of Notch1-IC, on the binding that occurs between Notch1-IC and RBP-Jk, both in vitro and in vivo. By intrinsic fluorescence, we also determined that nitration could mediate conformational changes of Notch1-IC. The substitution of phenylalanine for tyrosine at residue 1905 in Notch1-IC abolished the nitration of Notch1-IC by LPS. Overall, our data suggest that an important relationship exists between LPS-mediated inflammation and the Notch1 signaling pathway, and that this relationship intimately involves the nitration of Notch1-IC tyrosine residues.

Key Words: LPS • Nitric oxide • Notch

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