Leukotriene D4 mediates survival and proliferation via separate but parallel pathways in the human intestinal Epithelial cell line Int 407.

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We demonstrated previously that leukotriene D-4 (LTD4) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)epsilon-dependent stimulation of the mitogen-activated protein kinase ERK1/2. Our current study provides the first evidence that LTD4 can activate 90-kDa ribosomal S6 kinase (p90(RSK)) and cAMP-responsive element-binding protein (CREB) via pertussis-toxin-sensitive G(i) protein pathways. Transfection and inhibitor experiments revealed that activation of p90(RSK), but not CREB, is a PKCepsilon/Raf-1/ERK1/2-dependent process. LTD4-mediated CREB activation was not affected by expression of kinase-dead p90(RSK) but was abolished by transfection with the regulatory domain of PKCalpha (a specific dominant-inhibitor of PKCalpha). Kinase-negative mutants of p90(RSK) and CREB (K(-)p90(RSK) and K-CREB) blocked the LTD4-induced increase in cell number and DNA synthesis (thymidine incorporation). Compatible with these results, flow cytometry showed that LTD4 caused transition from the G(0)/G(1) to the S+G(2)/M cell cycle phase, indicating increased proliferation. Similar treatment of cells transfected with K-p90(RSK) resulted in cell cycle arrest in the G(0)/G(1) phase, consistent with a role of p90(RSK) in LTD4-induced proliferation. On the other hand, expression of K-CREB caused a substantial buildup in the sub-G(0)/G(1) phase, suggesting a role for CREB in mediating LTD4-mediated survival in intestinal epithelial cells. Our results show that LTD4 regulates proliferation and survival via distinct intracellular signaling pathways in intestinal epithelial cells.


Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)45577-45585
JournalJournal of Biological Chemistry
Issue number46
Publication statusPublished - 2003
Publication categoryResearch