The Inflammatory Mediator Leukotriene D4 Induces β-Catenin Signaling and Its Association with Antiapoptotic Bcl-2 in Intestinal Epithelial Cells

• Published in: The Journal of biological chemistry 2006-03, Vol.281 (10), p.6776-6784
• Main Authors: Mezhybovska, Maryna, Wikström, Katarina, Öhd, John F., Sjölander, Anita
• Format: Article
• Language: English
• Subjects: Apoptosis - physiology; beta Catenin - genetics; beta Catenin - metabolism; Cell Line; Cell Survival; Cell Transformation, Neoplastic - metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Humans; Intestinal Mucosa - enzymology; Intestinal Mucosa - metabolism; Leukotriene D4 - physiology; Microscopy, Fluorescence; Mitochondria - metabolism; Protein Transport; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction - physiology; TCF Transcription Factors - biosynthesis; TCF Transcription Factors - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M509999200

Increased levels of the inflammatory mediator leukotriene D4 (LTD4) are present at sites of inflammatory bowel disease, and such areas also exhibit an increased risk for subsequent cancer development. It is known that LTD4 affects the expression of many proteins that influence survival and proliferation of intestinal epithelial cells. We demonstrate here that after LTD4 exposure, β-catenin translocates to the nucleus where it signals activation of the TCF/LEF family of transcription factors. These events are mediated via a phosphatidylinositol 3-kinase-dependent phosphorylation of the inhibitory Ser-9 residue of glycogen synthase kinase 3β. We also show that in the presence of LTD4, free β-catenin translocates to the mitochondria where it associates with the cell survival protein Bcl-2. We hypothesize that LTD4 may enhance cell survival via activation of β-catenin signaling, in particular, by promoting the association of β-catenin with Bcl-2 in the mitochondria. Similar to Wnt-1 signaling, LTD4 signals an increased level of free β-catenin and elevated TCF/LEF promotor activity. This work in intestinal epithelial cells further lends credence to the idea that inflammatory signaling pathways are intrinsically linked with potential oncogenic signals involved in cell survival and apoptosis.