Editors' ChoiceInflammation

NO Link Between Notch and Inflammation?

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Science Signaling  29 Apr 2008:
Vol. 1, Issue 17, pp. ec154
DOI: 10.1126/stke.117ec154

Both nitric oxide (NO) and Notch signaling have been implicated in inflammation, although the details of their roles have not been determined. A study by Kim et al. presents evidence that NO may repress Notch signaling by nitrating the Notch intracellular domain (NICD, a transcription factor that is released from the membrane and translocates to the nucleus upon stimulation of the Notch pathway). Immortalized macrophages were exposed to lipopolysaccharide (LPS), a bacterial cell wall component, to induce an inflammatory response, and the effect on expression of three different NICD-responsive reporter genes was measured. The expression of each reporter decreased in cells exposed to LPS and in cells treated with the NO donor S-nitro-N-acetyl-penicillamine (SNAP). LPS-treated cells secreted NO into the culture medium, and pharmacological inhibitors of NO synthesis blocked the LPS-induced repression of the reporters. The amount of NICD bound to the reporter promoters decreased as the extracellular NO concentration increased, and high NO concentrations prevented NICD from associating with its DNA-binding partner RBP-Jk. An antibody that recognizes nitrotyrosine confirmed that nitrated NICD was present in extracts from LPS-treated cells. The fluorescence emission profile of NICD indicated that its conformation changed upon exposure to NO, so the authors postulated that nitration represses NICD activity by rendering it incapable of binding to its transcriptional coactivator(s). It had been previously reported that the glycosylation state of the Notch extracellular domain affects its ligand-binding activity, and now it appears that activity of the intracellular domain can also be modulated by covalent modification.

M.-Y. Kim, J.-H. Park, J.-S. Mo, E.-J. Ann, S.-O. Han, S.-H. Baek, K.-J. Kim, S.-Y. Im, J.-W. Park, E.-J. Choi, H.-S. Park, Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide. J. Cell Sci. 121, 1466-1476 (2008). [Abstract] [Full Text]

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